The game begins with Hayden, an American special forces agent, sent to a military-esque compound in the fictional Soviet Nation of Lasria. He tries to back out of his mission before it has hardly begun, but his superior, communicating via radio, says that he is "past the point of no return." Hayden makes short work of all enemy resistance and finds himself face to face with his target, a fellow agent named Viktor, tied to a chair. Viktor is under the impression that Hayden is here to rescue him. He even tells him information to aid him on his way. Hayden swiftly puts a bullet right through his skull. After reporting that he has completed his mission, his superior decides to send him after Mezner, the man responsible for the Technocyte infection that has been ravaging the country of Lasria. Hayden proceeds through the compound; defeating several dozen more soldiers and even a helicopter, as well as planting C4 charges throughout the compound. Hayden then finds himself face-to-face with a seven foot tall metal creature of some sort (Nemesis). Hayden attempts to defeat the monster by way of firing an RPG at it, but the metallic figure stops the RPG mid-air and redirects it at Hayden. Hayden is forced to jump off a cliff to avoid the missile, and upon waking up, once again finds himself face to face with his target, this time laying on the ground as Mezner lectures him. As Hayden attempts to reach for his gun, Nemesis appears and stabs his right shoulder. Upon instruction from Mezner, it transfers the infection into Hayden via the wound. It appears that he was going to kill Hayden, but Hayden quickly detonates the C4 charges set earlier and manages to escape.
He then arrives at a radio station to contact his superior for further instructions, with his right arm's skin degenerated and exposed flesh. The superior is informed of the situation and tells Hayden to meet up with their sleeper agent, Yargo Mensik, to obtain boosters for the infection. Soon, he hears the footsteps of an enemy soldier and attempts to ambush him. The soldier quickly gets the upper hand and pins Hayden down. Hayden's infected arm then produces the Glaive, and slits the soldier's throat. Another soldier enters the shed and shouts that he has "found him!" over his radio, only to be brutally decapitated by the Glaive as Hayden throws it at him. Hayden continues along the coast, slowly gaining new abilities with the Glaive as the infection progresses and produces some kind of metal that eventually surrounds his right arm completely, encountering both soldiers, Haz-Mat soldiers in masks, and the infected (people infected with the virus and driven mad from pain.) Eventually Hayden encounters a massive, ape-like monster with flesh covered in the same type of metal as Hayden's infected arm. After a short conflict in which both Hayden and the creature come to a neutral standstill, the monster is called back by some sort of signal.
Hayden then makes his way further up the coast to a temporary military base set up in an abandoned pier. After fighting his way closer to the main building he overhears a Lasrian soldier calling for help on a radio as he is slowly driven insane by the infection. Hayden then delves into the basement area and after taking care of several infected makes his way to the roof. It is there he gains a new mutation ability and finally finds Yargo. He tells Hayden that his orders have been updated and gives him the booster to help slow the infection. Hayden refuses and asks about the new intel.
Yargo tells him that he and the Agency believe that Mezner wants to recapture the infected which Hayden released when he detonated the Lasrian military base. Mezner had retrieved an old transmitter which emits a signal that attracts Technocyte creatures to its location and concealed it within an old church. We also learn that Nadia, a woman Hayden knows, is also working for Mezner. Hayden moves on towards the church to destroy the transmitter all the while taking care of legions of both Lasrian soldiers and infected. Being infected himself Hayden is also attracted to the transmitter. On his way he fights a Jackal Tank and is knocked out after a fight with an agile, humanoid Technocyte creature. He wakes up at night and continues his mission. Eventually, he makes it into the church building where Hayden and the Colossus have one final showdown, after killing the Colossus he makes his way into the catacombs and finds the transmitter. Nadia, who has a deep- rooted hatred for Hayden after his last meeting with her, confronts him. She escapes and leaves him to fight his way through a swarm of infected and escape before the C4 he set goes off.
After making contact with his superior again he is told that Mezner has some infected on a ship and is trying to export the Technocyte virus to the rest of the world. After fighting and hijacking another tank Hayden pushes to the coast and hitches a ride on a helicopter to the ship. Fighting the crew, he makes it into the cargo hold and accidentally releases a highly evolved Technocyte monster which sinks the ship. Hayden escapes with his life but Yargo has been found and captured by the military.
Hayden rushes back to Yargo's place all the while killing huge amounts of infected and a large power-armoured soldier. He finds the place but Yargo has been moved to another location where Nadia is torturing him, demanding that he let her into "The Vault". His superior, seeing the horrible mess of things, contacts Hayden and tells him that he's coming to take over and to stand down. Hayden doesn't listen and goes to save Yargo anyway.
Making his way to the train station he fights through more evolved versions of the infected and even more Lasrian soldiers. He finds Yargo as well as the creature he let out of the ship. After killing it and mutating again he gets Yargo and attempts to use the booster, but Yargo tries to say something. Before Yargo can get the words out, Nemesis appears and forces them to split up. Hayden attempts to take Nemesis head on but he soon finds out he's still not strong enough to fight it. Mezner arrives and offers Hayden a chance to kill him, however Mezner has grown powerful enough to mentally control Technocyte infected victims, and begins to mentally overpower Hayden. In a last ditch effort, Hayden injects himself with the booster, which breaks Mezner's control while simultaneously preventing further mutations. Mezner tells him that he had the same booster and both he and Hayden were being prepared for the Technocyte's release. Hayden passes out and both the Nemesis and Mezner leave him for dead.
Hayden wakes up later with Yargo, who tells him that he laced the booster with Enferon, a chemical that kills the infected. He claims that he was worried that Hayden would turn out like Mezner because he had the same injections and the same infection, he also tells Hayden that he can get a suit similar to the Nemesis' in the same building; the Vosro Research Facility, where the Technocyte virus was made during the Cold War. Hayden saves Yargo by sending him through the ventilation system and makes his way down towards the labs where the other suit is kept. After killing hordes of Technocyte infested mutants and bypassing automated security systems, Hayden discovers the suit in an airtight chamber. He enters the room, shooting the lock as he goes so nothing can follow him inside. Just before he puts on the suit, Nadia is arrives outside the door and Hayden pleads with her to leave before things get worse than they already are. She says that she's in too deep to get out now and that she is taking Yargo to open the vault.
Hayden gets the suit and slaughters his way through infected and non infected alike, taking down 3 powered armour soldiers and finally finding Nemesis. In the final showdown, Hayden kills the Nemesis and learns that it was actually Nadia all along. She apologises for infecting Hayden and tells him Mezner is planning a worldwide transmission to spread the Technocyte virus everywhere, Hayden says that he can't stop him because the organization is in the way. Nadia then tells him that she knows he'll "...do the right thing this time", leaves him with the key to the vault, and then dies. Hayden then hijacks another Jackal tank and kills everyone in his path on his way to the vault.
He arrives at the entrance of the vault to rendezvous his superior (His name is revealed to be "Dixon" as seen on his uniform), who says he has made a deal with Mezner and gives him a booster "for the road". Hayden is outraged and stabs him in the neck with the booster, and tells him that he "likes it" [the infection] and goes to destroy Mezner. He kills all of the men under his superior's command and then enters the vault. Once inside, Mezner tries to convince Hayden to join him. This doesn't work and Hayden goes deeper into the vault. He then finds the source of the Technocyte, or at least the first known source: the submarine that appeared off the coast of Lasria, only Hayden finds out that the submarine was actually American (Either by accident or on purpose, we don't know; it is implied that the American government knew all along). After the final showdown with Mezner, and the Technocyte Hydra-like monstrosity he controls, Yargo arrives to tell Hayden that the transmission is still going out. Hayden tries to fry the circuitry by using his glaive but before the dying Mezner, who is not quite dead yet attacks him one last time stunning his right arm, before telling him "You are one of us now". Hayden then catches the now electrified Glaive with his left hand and impales Mezner's skull with it. With the transmission finally halted, the game ends with Yargo saying "That was how it started, the irony of this disease, that in all the others it made evil, but for him it saved his soul".