In the midst of the Great War, the German research organization Group 935 was tasked with creating powerful and revolutionary new weaponry to ensure the victory of the Central Powers, including the prototype Mauser C96 pistol designed by Dr. Ludvig Maxis and deadly armory for the German forces. In September 1917, Dr. Maxis and his partner Dr. Edward Richtofen led an archaeological excavation in the trenches of Northern France, with Maxis promising Group 935's leaders it was the location of an unknown and enigmatic new element. During the mining, a mysterious and ancient ruin was uncovered beneath the battlefield, as well as the new element Maxis spoke of, which was classified as number 115 on the periodic table. The group planned to use the powerful new element as a power source for new weaponry in the Wonder Weapon program, and installed a series of conversion generators that utilized 115 to create localized energy fields. To their surprise, the energy fields acted as portals bringing forth machinery of indeterminate origin, leading Maxis to believe that the conversion of the element was capable of creating a crease in space and time.

As the excavation continued on, more wonders were discovered by 935, such as an ancient box capable of delivering weapons from various time periods, making Maxis more so confident of 115's time-altering properties. As 115 was excavated, Dr. Richtofen took part in the creation of four giant mechanical robots powered by the element, with Group 935 planning to deliver them to Germany's army for usage in battle. During the construction, Richtofen noticed the increasing changes in Maxis, such as paranoia and mental psychosis. Eventually, the symptoms worsened as a child named Samantha began communicating with Maxis, begging him to be freed from a realm known as Agartha. Due to her constant interference with their work, Richtofen grew to despise the unseen voice and fear for his friend's own safety. The spike of German activity in France made the Allied forces fearful of what the Kaiser was planning, and began organizing an operation to investigate the activities of Group 935. Chosen by the Emperor himself for his leadership and victory at the Battle of Mukden, samurai warrior Takeo Masaki was to infiltrate the research team and seize all weaponry for the use of Japan. Meanwhile, after the ruins have been unearthed, many attempts were made at opening the main chamber of the mound using brute force, though all proved unsuccessful. However, after a gramophone was presented and played music to lighten the mood, the main chamber's seal revealed itself, where Maxis learned through the writings in the chamber of a device created by an ancient race known as "the Amplification Rod", which harnessed the energy of the Elemental Stones. Due to neither the stones nor the rod having been located, Maxis instructed Richtofen in creating four replica Elemental Staffs to continue efforts to find the real device.

When presenting the idea, Richtofen began to question Maxis' actions, believing the Amplification Rod to be a myth. Convinced of his insanity, he planned to report his mental instability to Group 935's leaders, while Samantha began to communicate more frequently with Maxis, now attempting to convince him of her being his future daughter. Maxis himself now feared for his own sanity. One night, as a team of soldiers were installing more generators, they reported seeing strange and ancient figures emerging from the mound and finding many of the men dead or missing by morning. As more figures emerged, now revealed to be corpses reanimated by Element 115's powers, the test site slowly became infected by the creatures, with Maxis himself slowly turning. The reports of the creatures provoked the United States to send Tank Dempsey to the test site to investigate the group's work, and acquire Dr. Richtofen as an HVI. Meanwhile, civl war-torn Russia did the same, believing the Germans had been gearing up to unleash a dangerous new weapon and sent Nikolai Belinski to undertake the mission. As the three soldiers made their way to the site, Richtofen attempted to preserve Maxis' mind and prevent it from succumbing to the disease, and removed his brain to be used in making a new psychical form for him.

After completing the operation, the four heroes meet and agree to put aside their country's allegiances to band together and survive the zombie attack and Group 935's mechanical robots, while being contacted by Samantha in the midst of battle begging to be released from Agartha. While Tank, Nikolai and Takeo agreed to help, Richtofen focused on creating a makeshift quadrotor drone using Maxis' brain, allowing him to live temporairly until a human body could be provided. Eventually, the four were able to open the portal to the Aether beneath the ruins, allowing Maxis to meet his future daughter and Samantha to be freed from controlling the zombies. Richtofen, Tank, Takeo and Nikolai were all rewarded greatly for their help, and the zombie population was contained. Months later, the war would end in an Allied victory after the signing of the Treaty of Versailles, and Group 935 would disband due to Germany's hefty loss.

21 years later, the world would once again be threatened by a second world war after Germany's chancellor and supreme dictator Adolf Hitler rose to power. Dr. Maxis, now returned to a younger and suitable human body, reunited Group 935 as an international German-led research team, and emerged as its head scientist. Rather than their previous goal, Maxis sought to use Element 115 to improve the human condition by developing advanced technologies, and enlisted Dr. Richtofen as his senior assistant rather than equal partner, much to his chargin. However, the group's goal immediately detoured due to a lack of funding, and Maxis regretfully turned to making a contract with the Nazi Wunderwaffe Program to use 115 as a power source for deadly new weaponry to help the Axis Powers win the war. Maxis hoped that after the war, the generous funds and Germany's ultimate victory would put Group 935 in a much better position to help the world.

Using a large supply of Element 115 found in global meteors, Maxis began a series of tests experimenting with 115 being used to power devices capable of teleportation, called MDTs, at the Der Riese facility in Lower Silesia. While majority of the tests failed, Richtofen and another 935 scientist, Dr. Schuster, conducted a successful test on their own by teleporting a walnut using a small amount of Element 115. Though Edward assumed it was a sign of progress, Maxis criticized the scientists for failing to work on their assigned experiments, which led Richtofen into thinking that Maxis planned to betray the scientists of 935 and claim their work as his own. Despite Maxis' displeasure, Richtofen and Schuster continued their research with the MDT device, and after a month of tests, Richtofen agreed to be teleported himself. But rather than appearing at the test site's mainframe, he arrived within a catacomb on the moon, where a large, triangular device known as the MPD was located. After touching the device, Richtofen began hearing a series of voices in his head, unknowingly gaining schizophrenia from the pyramid before being teleported away from the strange device. Arriving in an exotic shrine in the Himalayan jungles known as Shangri-la, Richtofen remained there for three weeks learning of a mysterious energy force and alien race known as the Vril.

Richtofen returned to the Der Riese facility with full knowledge of the MPD and the Vril, and with Schuster and other Group 935 scientists, spent two years building a top-secret moon base, Griffin Station, to study the device, which he now knew to be a dimensional gateway to the Aether. Placing Schuster and his superior, Dr. Groph, in charge of the facility, Richtofen continued his charade as Maxis' senior assitant, whom he planned to eventually kill and enter the Aether using the MPD to take control of it's energy. As Groph and Schuster toiled with the device, Maxis and Richtofen began a project to create Wonder Weapons for the Nazi Party. Using designs from the Japanese Rising Sun facility, Maxis created a weapon known as the Ray Gun, which ran on atomic cold cells powered by 115. Richtofen, meanwhile, harnessed the element's VIN electrical properties to create a weapon that fired bolts of electricity called the Wunderwaffe-DG2, a weapon so deadly even Maxis himself felt uneasy about it's mass-production. Nonetheless, he promised Richtofen it would be produced the front lines of the Waffen-SS, but his growing attraction with his secretary Sophia prevented him from doing so.

While other weapons were produced from several Group 935 facilities, such as the Quantum Entanglement Device made by Richtofen or the second generation Ray Gun created by Dr. Porter, Maxis focused his attention on the matter transference devices, hoping to manufacture them to the Wehrmacht granting German forces easy travel in the war. The initial tests failed, with test subjects either being killed or exposed to Element 115, resulting in their deceased cells being reanimated and becoming unresponsive zombies. However, the first successful test would be conducted after a dog had been sent through the device and failed to return to the mainframe, making Richtofen believe subjects were being sent through time as well, though Maxis rejected the idea for a lack of proof. While Maxis believed the MDT experiments to be failures, the Reichstag saw the creation of the zombies as another advantage in the war, forcing Maxis to carry out top-secret mind control research at a defunct theater in Berlin in an effort to control the zombies as an undead army.

Dr. Edward Richtofen tested Element 115 on living test subjects to create his own super soldiers at a Siberian facility. In his experiments, Richtofen used Takeo Masaki, Nikolai Belinski, and an unknown Mexican. After accidentally killing the Mexican through these 'tests', Richtofen replaced him with Tank Dempsey. Dempsey was the leader of a Marine Recon team, that was sent in to rescue Dr. Peter McCain, an OSS spy sent to infiltrate Group 935. The recon team had to find McCain in the Wittenau Sanatorium, in Berlin. The team was killed by zombies, and Dempsey was the only survivor of the mission. He was then captured and tested upon by Richtofen as a replacement for the Mexican. After Dempsey's attempted infiltration, Peter McCain and all other American members of Group 935 were killed to avoid any chance of spies. The testing affected each of the subjects' minds, making Dempsey extremely aggressive, quieting Takeo into only reciting Japanese proverbs, and making Nikolai functionless without vodka. It also had the side effect of erasing their recent memories, making them forget how Richtofen captured them and what he did to them. There was also an outbreak at a German airfield.

Unbeknownst to Maxis, Richtofen had already mastered teleportation while Maxis was still trying to master it. Maxis was getting frustrated that he could not send a subject to the mainframe and so used his daughter Samantha's dog, Fluffy, as a test subject but once again failed. The dog was teleported, but instead of being destroyed like past test subjects, she was zombified (the first Hellhound). When Samantha came running in and started questioning her father about what happened to her dog, Maxis tried to stop her and get out of the room. Richtofen then followed through with his previously-planned betrayal by locking Maxis and his daughter in the room with the Hellhound, he then activated the teleporter which he then thought killed Samantha and Maxis.

Little did Richtofen know that Maxis' teleporter actually worked and sent Samantha to the Moon base. In her fear, she ran into the M.P.D. and became the one to control the zombies. When Richtofen was informed of what had occurred he warned the pair of scientists about the Hellhound and then told them to find a way to get Maxis. When Maxis was found, they let him approach his daughter to calm her down. After apologizing for his actions, Maxis told Samantha to kill all of the Group 935 members for betraying him and was subsequently shot. Being near the M.P.D when killed allowed Maxis's soul to be captured by it and sent into the Aether. Samantha then proceeded to fulfill her father's request by unleashing the zombies.

Richtofen retreated with Dempsey, Nikolai and Takeo to Shi No Numa to think things through. When the zombies attacked Richtofen he realized that Samantha will stop at nothing to seek revenge. Richtofen planned to recover all of the equipment to take control of the zombies. In a desperate attempt to retrieve the necessary equipement for his plan and to accomplish his wishes on mass-producing the DG-2, Richtofen then took the group to Der Riese, which had been abandoned since the zombie takeover. The group used the Wunderwaffe DG-2 to overcharge the teleporter, making it capable of time travel. Richtofen was apparently unaware of this possibility until he tried it. He seemed unconcerned that he and his partners have been teleported to an abandoned theater in Berlin, Germany (Kino der Toten).

Sometime prior the characters' arrival at the Soviet Cosmodrome, an Ascension scientist Yuri Zavoyski was transferred from Project Mercury (Gersch Device) to work on sending monkeys into space, much to his dismay. His transfer was caused by his superior, Gersch, who he holds a grudge against after the relieving of his duty from Project Mercury. As Gersch is working on Project Mercury, his staff is working on Project Thunder (Thundergun). Yuri notices the teddy bear and the Matryoshka Dolls and wonders how a child could be let into the station. The child Samantha then slowly drives Yuri insane. Yuri, in his state of insanity, finishes the Gersch Device and has Gersch activate it, letting in the zombies and trapping Gersch. Yuri soon realizes his mistake and screams.

After the events of Kino der Toten, the main characters somehow reach the abandoned Soviet Cosmodrome. The characters then hear Gersch, who tells them that the mechanism must be repaired. He is referring to the Casimir Mechanism, which must be repaired by completing different tasks. After all of the tasks are completed and the mechanism is repaired, Gersch is freed, leaving Samantha free to be ridden of in the Aether.

While the events of Ascension are occurring in Russia, the events of "Five" are also unfolding in the Pentagon. A piece of Intel reveals that all Wunderwaffe materials were to be moved to American-controlled installations. As a mainframe is visible behind one of the windows in "Five", it is apparent that it was moved there as per this order. While John F. Kennedy, Robert McNamara, Fidel Castro, and Richard Nixon are negotiating, zombies break into the Pentagon with only the four of them left to fight them. While fighting, they call Dempsey, Takeo, Nikolai, and Richtofen using three red telephones spread across the Pentagon. Their calls show that they're running out of ammo and will soon be defeated.

As they continue fighting, the three start regaining their memory. Takeo is the first to remember, and remarks to himself that some day when the group is finished fighting zombies, Richtofen will get what he deserves. He also shows his observations of the other two. He believes Nikolai drinks vodka because he wishes to forget the past and can't function when he remembers it, perhaps meaning Nikolai is beyond hope. Tank, on the other hand, is slowly making progress, as he remembers that he'd seen Richtofen before the fight at Shi No Numa. Takeo notes his shifting memories and believes Dempsey is finally remembering what Richtofen did to him.

George A. Romero stumbled upon Group 935's research while making a WWII film. He and the cast took a ship out to an abandoned lab in Siberia. After he and the ship's crew were zombified, only the cast, made up of Sarah Michelle Gellar, Robert Englund, Danny Trejo, and Michael Rooker, remained. This set the stage for Call of the Dead. After the Casimir Mechanism was completed in Ascension, it overloaded the teleporter and sent the original characters to a Group 935 facility in Siberia, where they were trapped behind a locked door. The celebrities then proceeded to help them escape to Paradise. Richtofen then asked the celebrities to help him obtain the Golden Rod, which they did. Richtofen thanks the group by giving them the Wunderwaffe DG-2 to help them fight the zombies. In reality, the group could've escaped after the security system was disabled. It is unknown what became of the celebrities after helping the group escape.

Shangri-La, however, does not live up to its name, as its inhabitants have all been zombified before the group's arrival. Richtofen now states that this was the last step to controlling the world before he is teleported there. The temple houses a mining facility filled with Element 115, explaining the inhabitants' zombification.

Prior to the group's arrival at Shangri-La, two explorers, Brock and Gary, went on an expedition to prove their theories on Agartha. Brock later figures out that the temple wasn't built by an ancient civilization, but by people in the modern era interpreting it. After investigating the temple, the pair accidentally activated the temple's time travel and died in the resulting zombie attack. The group travels back in time and helps the pair survive. The pair's changing fate is illustrated by the radio that changes message and location as the group helps them. When the group finally create the Focusing Stone, it lands on an altar with Richtofen's name on it, meaning the temple was in fact another Group 935 facility and explaining Richtofen's knowledge of its location. The two explorers are then sent back to the moment they discovered the temple, indicating that they're stuck in a never-ending loop.

Now in possession of both the Golden Rod and the Focusing Stone, Richtofen believes he can now control the zombies. The group then travels to Area 51 so they can get to the Moon via a teleporter to Griffin Station. When the group reaches Area 51, it is already overrun. Due to the Element 115 on the Moon, astronauts and scientists sent there have been zombified before the group's arrival. The people killed by Groph and Schuster contributed even more to the zombie horde.

Meanwhile, a group of radiation scientists investigate the ruins of a former nuclear test site in Nevada, where the undead begin to attack, forcing the surviving scientist, Marlton Johnson, to send a distress flare signal intercepted at Hangar 18 before locking himself in a bomb shelter. CIA and CDC agents were then dispatched into the site in a rescue attempt, resulting in a struggle with the zombie population located there as Richtofen enacts his grand scheme on the Moon.

Richtofen then has the group complete the MPD When the device is completed, it opens up to reveal Samantha Maxis suspended in the air. As it turns out, the device acts like a prison and keeps her cryogenically frozen so she can be used to control the zombies. Richtofen goes to a terminal to power up the Golden Rod (or V Device) and the Focusing Stone, which he fuses together. However, he encounters Dr. Maxis inside the terminal, who tries to stop him. Richtofen switches souls with Samantha to gain control of the zombies. Richtofen finally thinks everything has gone his way, until Takeo, Dempsey, and Nikolai decide to stop him. Dr. Maxis, sensing Richtofen's betrayal, prepared a backup plan in case Richtofen got this far. The group then launches three missiles located on the Moon, one of which impacts the nuclear testing site, destroying the Earth's ozone layer in the hopes that it will sever the link between to the Aether, thereby greatly lessening the damage Richtofen could cause. Unfortunately, the calculations were made in haste, resulting in catastrophic destruction.

The missile launch leaves the Earth a post-apocalyptic crumbling wasteland, littered with undead hordes as civilization begins to collapse. As survivors begin to band together to form small human communities and shelters to protect themselves from the now global-undead threat, Maxis realizes the failure of his original plans due to hasty calculations and begins contacting survivors to help him with his "Plan B"; to activate global polarization devices and open a gateway to the Aether, where he would overpower Richtofen and use its energy to heal the Earth. To complete his plans, Maxis began using electronic devices on Earth to communicate with survivors, and came into contact with a survival camp at Jackass Flats in Nevada to polarize a spire located there. Unbeknownst to his followers, Maxis planned to comandeer the Aether's energy for his own use to open the gateway to Agartha, which would ultimately destroy the Earth and its people.

Richtofen, unsatisfied with his limited power to the undead, planned to activate these polarization devices as well, which would grant him further manipulation of both zombies and humans, and additionally mend "the Rift", a direct gateway to Agartha that would eternally damn the soul of Samantha Maxis. Limited to communicate with only those capable of hearing the voices of the Aether, Richtofen began his own plight and quest for unlimited power.

Meanwhile, Marlton Johnson emerges as the sole survivor of the events in the nuclear test site and meets Abigail "Misty" Briarton in an abandoned town in Hanford where they find two more survivors, Russman and Samuel J. Stuhlinger, who have commandeered a robotic bus they have used for transport. There, the four survivors are contacted by Maxis, who reveals the town is a location of a polarization device required for his plans. At the same time, Richtofen contacts Samuel, who has previously eaten zombie flesh resulting in him being able to hear Edward in his head, instructing him to foil Maxis' plans by activating the tower in his favor, beginning the race for power between the Germans.

Regardless of their choice, the group is teleported by Richtofen to the crumbled city of Shanghai, China, where they began realize that throughout the planet, very few survivors live in the ruins. In an abandoned building, Maxis regained contact, hoping to gain control of the second tower located there, while Richtofen blackmailed Samuel into helping him acquire the device's power as well, threatening to reveal to his allies about his dangerous secrets.

Once the second polarization device had been activated by either of the Germans, the group managed to escape the building they were trapped in. Eventually, Russman leads the group out of the crumbling city of Shanghai, and the four began a month-long travel through the remains of Europe and Africa to reach the Rift, hoping to find answers about the unseen forces commanding them. In Southern Angola, Maxis once again contacted his corporeal allies, imploring them to activate the last tower in his favor. Meanwhile, Samuel was tasked for the same objective by Richtofen, as it was too the last tower he needed to mend the Rift and gain his unlimited power.

If the player decides to follow Maxis' Easter Eggs in all three maps and polarize the towers in his favor, a portal to the Aether will open and allow Maxis to become the controller of the zombies and the dimension's energies. He will then proceed with his plans to open Agartha (revealing himself to be just as evil as Richtofen, and announcing that in the process he will destroy the Earth and its surviving inhabitants) and reunite himself with his daughter, Samantha, after returning Richtofen to the physical world spawned as a blue-eyed zombie.

If the player decides to follow Richtofen's Easter Eggs in all three maps and polarize the towers in his favor, the Rift will be mended, eternally damning Samantha to Agartha and allowing Richtofen to retrieve full manipulation of the Aether's energies. With the Earth as his personal playground and Maxis to cease his very existence, Richtofen is now able to leave the Aether at will and uses the body of Samuel Stuhlinger as his physical host.

Unbeknownst to the both of them, Samantha had actually travelled back in time and started communicating with her future father around the time Element 115 was first discovered, possibly bringing the Zombies with her. After making the four original characters complete a series of tasks to open Agartha, Samantha is finally freed and returned back to her time. However, the younger Maxis, now in a robotic form due to succumbing to the illness earlier, flies into the portal with the younger characters, creating a paradox leading to unknown results. Whether the portal sent the young characters to the present or if it created a paradox that led to the zombies storyline never happening (as hinted by the ending cutscene of Origins) is currently unknown.