Frank West, a photojournalist, sneaks into the town of Willamette, Colorado, to investigate why it has been sealed off by the National Guard. Discovering it is suffering from a zombie outbreak Frank informs his helicopter's pilot, Ed Deluca, to bring him onto the rooftop helipad of the town's shopping mall, requesting he returns for him in exactly 72 hours. Upon landing, Frank meets a mysterious man named Carlito Keyes who hints to the outbreak being far more than it seems. After witnessing a group of survivors fail to hold back zombies from entering via the mall's front entrance, Frank takes safety in the mall's security room with three other members of the group - Brad Garrison, a DHS agent, his rookie partner Jessie McCarney, and mall janitor Otis Washington, who welds the room's door shut. Seeking to continue his investigations, Brad leaves via an air duct. Following after him, Frank finds Jessie sneaking up behind him before he re-enters the mall, who after injuring her ankle, asks him to find Brad after he was spotted being pinned down in a gunfight. Although he agrees to help, Frank confronts Brad over what is going on after his attacker turns out to be Carlito. The DHS agent agrees to explain on the condition that Frank helps him to track down a scientist called Dr. Russell Barnaby, a man Frank had photographed before the barricade on the front entrance failed. Agreeing, the pair track down Dr. Barnaby to a barricaded bookstore, whereupon he refuses to leave without a secure escape route from the mall.
The next morning, Carlito captures Dr. Barnaby, and upon being spotted on the security room's monitors suspending him over a group of zombies, forces Brad and Frank to rescue the doctor, the former being wounded in the effort. While seeking medicine for Brad in from the supermarket pharmacy, Frank rescues a young woman from the store's crazed manager Steven Chapmen, who Frank is forced to kill in self-defense; afterwards, the woman runs off after Frank recognises her from earlier and attempts to question her. After tracking her down via the security room's monitors, the woman identifies herself as Isabella Keyes, Carlito's sister. Agreeing to arrange a meeting with Carlito, so Frank can learn the truth behind the outbreak, Isabella turns up at the rendezvous with a wounded shoulder, after her brother shot her out of anger. Taking her back to the security room, Isabella identifies Dr. Barnaby as the head of an American research laboratory in her hometown of Santa Cabeza, in Central America. Succumbing to the infection that caused the outbreak, Dr. Barnaby reveals that he was attempting to find the means to mass-produce cattle, but accidentally mutated a local wasp species, causing them to impregnate any victims of their stinging with parasitic larvae, killing their host and causing them to be “zombiefied” when one of these matured in the brainstem. A mutated wasp queen soon escaped the laboratory, turning the whole population of the town into zombies, effectively forcing the U.S. government to cover up the incident by sending in Special Forces to exterminate the zombies and any witnesses of their livestock research. Outraged upon learning about the massacre, Carlito released the mutant wasps in Willamette out of revenge, luring Dr. Barnaby to the mall via blackmail in order to kill him with the very zombies he had helped to create. After divulging the truth, the doctor soon becomes a zombie, biting Jessie before Brad kills him.
Isabella soon reveals that Carlito plans to cause a nationwide zombie pandemic, by setting off several charges of explosives in the maintenance tunnels beneath the mall, the resulting detonation propelling immature queen larvae into the stratosphere and across the United States. Frank quickly recovers the bombs and brings them outside into the open, where they explode harmlessly, while Brad pursues Carlito, injuring him in a fight, but unable to stop him escaping while succumbing to further injuries and eventually transforming into a zombie. Visiting Carlito's hideout, Frank and Isabella attempt to shut down a jamming device being used within his laptop, only to find they need the password for it. Finding Carlito being dragged away by the mall's now deranged butcher Larry Chiang, whom Frank defeats. Too gravely injured, Carlito passes on a locket to Frank for his sister, leading him to promise to expose the Santa Cabeza massacre to the world. After learning of her brother's death, Isabella figures out the password to Carlito's laptop through her locket, and shuts down the jammer. Jessie soon calls for help, only to learn that Special Forces are being sent in to cleanse the town. Frank soon catches up with her, finding she had succumbed to the infection and killed two guards sent to capture her, promptly killing her as a result, while finding a note from Otis stating that he hijacked a military helicopter and flew to safety with the survivors that had managed to be saved. After hiding out in Carlito's hideout, Isabella opts to remain at the mall, forcing Frank to head for his rendezvous with his extraction. As Ed arrives on time, a stowaway zombie attacks him, causing him to crash into the mall's central park. Slumping to his knees in defeat, Frank finds himself unable to do anything, as a group of zombies slowly approach him from behind.
Isabella comes to his rescue, saving him at the last moment. Passing out, he soon comes to in Carlito's hideout, whereupon Isabella tells him that he had been infected and has 24 hours before he becomes a zombie. Believing she may be able to manufacture a cure, Frank finds himself scavenging for the items she needs from the mall, in order to assemble a symptomatic treatment that can temporarily halt the development of the parasites. Before he leaves, the pair access Carlito's laptop and discover documents indicating that he has placed 50 similarly treated, larvae-infected children with foster parents across the country. While developing the treatment, the hideout's generator fails, forcing Frank to go to the clock tower in the mall's park to retrieve another one. While there, he discovers an underground tunnel filled with zombies and reports about this to Isabella, as she synthesizes an anti-zombie pheromone from the treatment's leftover ingredients. The two quickly make their escape from the mall, but find the other end of the tunnel guarded by the military. Overpowering the guards and stealing their jeep, the pair soon find themselves pursued by a tank, which Frank manages to disable using the jeep's mounted machine gun. Brock Mason, the leader of the Special Forces, soon emerges from the tank, and reveals that he led the original cleanup operation in Santa Cabeza. Just before he can aim the cannon towards the pair, the tank's auto-targeting mechanics activate and direct it towards an incoming horde of zombies, distracting Brock and allowing Frank to close in and defeat him in hand-to-hand combat.
An epilogue reveals that Frank and Isabella managed to escape Willamette, with Frank reporting on the incident, forcing the U.S. government to admit partial responsibility for the livestock research program and the Santa Cabeza incident, but blaming the Willamette outbreak on terrorists, while leaving Carlito's infected orphan plan to remain neither confirmed nor debunked.
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