Set between the events of the second and third game, Chase Carter, Jesse Metcalfe, and his camerawoman Jordan Blaire document a chaotic zombie outbreak in East Mission, Oregon. With the city largely evacuated, the government — operating a group called FEZA, the Federal Emergency Zombie Agency — establishes a guarded zone where infected are given the antiviral drug Zombrex to prevent their transformation. Yet, at the core, the Zombrex fails to take effect, and a wave of people begins to turn. In the confusion, Jordan manages to escape the city, while Chase is left behind.
Chase endures the initial onslaught alongside Crystal O'Rourke, Meghan Ory—an experienced loner who was infected in a previous outbreak and has not taken the government-administered Zombrex—and Maggie, Virginia Madsen—a grieving mother whose daughter was infected and then killed, leaving her in a state of delusion and denial. When Maggie explains that her daughter took the Zombrex, while Crystal carries her own, Chase theorizes that this could be a new strain that is resistant.
Chase reaches out to Susan Collier, Carrie Genzel, a news anchor outside the city who is covering the outbreak, along with Frank West, Rob Riggle, explaining his theory. In the meantime, Jordan reaches a military safe zone overseen by General Lyons, Dennis Haysbert, and Dr. Norton, Gary Jones.
Taking refuge in a pawn shop, Chase, Crystal, and Maggie encounter a group of anarchist bikers led by Logan, Aleks Paunovic, who have infiltrated the city to exploit the chaos. Jordan contacts Chase from outside and learns that the government plans to firebomb the city. Chase goes on the air to deny the government’s cover story. Witnessing Crystal administering her personal Zombrex needle, Chase realizes the infection isn’t inherently resistant, while Jordan investigates the safe zone. Jordan informs Lyons about Chase’s theory and is secretly given the location of a warehouse where the government’s Zombrex is kept. By providing Crystal with a test to compare the government Zombrex against Crystal’s own supply, they prove the government batch to be defective.
Chase broadcasts Crystal’s test, and public outrage forces Lyons to postpone the firebombing. However, the warehouse is revealed to be Logan’s hideout, where he has captured numerous zombies. Believing her daughter to be among them, Maggie willingly lets herself be bitten while embracing the thought. Logan captures Crystal and reveals his intent to bomb the city’s walls and spread the outbreak further. In the ensuing fight, Logan’s men are killed, and Logan himself is bitten and infected by a zombie. Meanwhile, Lyons addresses a press conference, accusing Norton of distributing defective Zombrex. Lyons later tells Jordan that he sent an evacuation team to rescue Chase, but found no survivors; Jordan realizes Lyons’ deception when Chase calls shortly afterward.
Lyons then announces to the press a plan to implant a Zombrex chip in the infected that would keep them controlled, but would require yearly administration. Before he leaves, Norton warns Jordan that the chips would allow the government to track the infected. Jordan notices a military truck from the day before carrying those chips and concludes that the government orchestrated the outbreak as a pretext to deploy them. Crystal and Chase reach the city wall, pursued by zombies and a transforming Logan, who intends to bomb the wall. Chase and Crystal kill Logan and are taken into the safe zone, where Crystal is implanted with the chip. Norton is killed as part of the cover-up, and Jordan is captured, but not before leaving her phone for Chase to find. As the city is firebombed, Chase and Crystal uncover the government’s true plans.
