Set between the events of Dead Rising 2 and Dead Rising 3, the story follows online reporter Chase Carter and his camerawoman Jordan as they cover the stories of the people inside of the walled-in quarantined area in the fictional town of East Mission, Oregon, as the government (running an organization called FEZA—Federal Emergency Zombie Agency) attempts to contain a viral outbreak that turns people into ravenous zombies.

An anti-viral drug called Zombrex, which keeps the virus at bay, is being administered to those infected. When it becomes clear that the drug is no longer effective and a zombie outbreak purges the town and infects its inhabitants, Chase, Jordan, grieving mother Maggie, and survivor Crystal battle their way out of the city before it gets firebombed.

Throughout the film, it is revealed that the Army implanted defective Zombrex drugs in a refugee center to start another outbreak so that the government can be allowed to plant government-mandated Zombrex chips on the infected to track them, framing FEZA for giving bad Zombrex to the infected. The coin that Jordan gave to Chase to open a newspaper vending machine at the beginning came in handy when she placed evidence of the Army sabotaging the Zombrex inside the vending machine for him to find.

When General Lyons figures out that Jordan and Norton are aware of the Army's actions, he has his men capture them to cover up the truth. In the end, Chase and Crystal manage to survive and get out of city, and Jordan manages to get footage proving the Army's complicity in the new outbreak to Chase, who finds it in the newspaper vending machine; the same footage shows her being taken into custody by the U.S. government, who then implant tracking devices on people who are infected.

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