A young biker is filling her motorcycle with gas at the gas station as a couple of hitchhikers are accosted by a zombie mob that would've bitten them had the biker not driven up, beheaded one zombie, and taken down the rest with her bare hands. She introduces herself as Bailey Matheson and asks where she can find a helicopter. After being directed to an abandoned military base, she gets on the helicopter and goes to the Philippines.
Once there, she cautiously makes her way around the island while trying not to get bitten. She enters a hotel overrun by zombies, including one that escaped the military's grasp before it could be burned. The zombie, a rough hotel owner with a thirst for blood, tells her that most of the inhabitants are infected with a virus the military called Death One and that he got the virus when one of two terrorists that stole the virus got infected before checking in to the hotel. The military burned a few corpses in the area when they found the guy's corpse, but he escaped when the virus took effect.
Bailey then goes to a funeral home where the military burned the terrorist. Seeing a hexagonal casket halfway inside an oven, she tosses it out. The funeral director, still himself, tells her that the military failed to follow health and safety protocol when burning the infected bodies at his funeral home. She demonstrates the explosiveness of gunpowder by throwing some spilled gunpowder into the oven and apologizes for the door coming off in the explosion when the oven was lit.
Upon leaving the funeral home, she encounters a zombie that picks a fight on her. Following a brawl, Bailey earns his respect by beating him in combat, and they become friends and get to know each other. Bailey learns that he got infected while helping some soldiers take down zombies and he doesn't wish to go on like that. Erin agrees to help him to the best of her ability.
They enter the research facility where Death One was being created when that serum got stolen. Bailey takes what's left of the samples before she and the zombie, who calls himself John, go back to the helicopter. Once there, the duo is confronted by a zombie mob. After incapacitating the mob (with John chomping on a few brains to sustain himself, all while wishing he didn't have to rely on tissue to survive anymore), the duo takes the helicopter back to the United States.
They reach the Rocky Mountains, where they find Kenny and Patricia taking refuge. Kenny, suspicious of the undead, tries to kill John, but Bailey assures him that John comes in peace. Bailey explains that she's trying to find a doctor that can cure John's condition. Kenny and Patricia agree to help, with Kenny warning John to stay away from human brains if he wishes to sustain himself. John agrees, and the two groups get in their helicopters bound for Philadelphia.
Philadelphia is chaotic, with the groups having to deal with the living dead inside the local cemetery. John eats another zombie's brains, and when Kenny yells at him for it, John assures him that since his victim wasn't human anymore, his brains couldn't possibly be called human brains. Kenny backs off, and they board the helicopters again. They go to New York City, where Peter and Francine are fighting another zombie mob. As they run out of ammo, Bailey and Kenny pick them up.
Peter is miffed that Bailey is in cahoots with a zombie, but he buys her story about how it may be possible for her to cure the zombies and that she too used to be prejudiced against all zombies until she met John. They find a newspaper at the airport where they land the helicopters, and they find out that Dr. Bolt had gone missing when his boat turned up with a dead policeman discovered on said boat. Following a search, they discover a copy of the letter Dr. Bolt sent to his daughter, Ann, which reached the New York City newspaper.
Acting on the tip, the party, in their helicopters, fly to Matool, the uncharted Caribbean island, after John eats the brains of several zombies via airport. Kenny remarks on how a zombie eating the brains of other zombies could be construed as cannibalism as the helicopters fly over the Caribbean sea.
They reach the island and find Ann working on a Cure for the contagion that infected the living dead on Matool. Ann and her boyfriend, Peter West (a former reporter for the New York City newspaper before the zombies took over), tell the party that they had heard about the outbreak while taking Bryan Curt with them to show the newspaper as evidence of their story. Brian reanimated during the story, and they turned back and returned to Matool, but not before Bryan broke down the door. Ann managed to put a strong sedative in him and had restrained him on an operating table with metal shackles attached to it.
Since then, she had decided to continue her father's work with Peter West. Bailey shows her samples of the Death One virus, and she agrees to try to reverse-engineer the virus so it can cure those infected by the virus. While she spends the next week working on it, the others hang out on the island while hiding from the zombies (and having John get his meals from charred corpses from inside the burned-down mission and the unmarked grave where the island's victims are buried. Ann tells him he can feed off the flesh of anyone but her father and tells him he had gray balding hair and a mustache and that all the corpses have their heads covered up so he'll have to remove the covering before feeding on their flesh.
John opens one corpse's head covering and finds Dr. Bolt's face underneath. He covers the good doctor's head again and marks the sheet in which he is wrapped with the name "DR. BOLT", but just to be sure, he removes the head coverings of others as well while trying to figure out who to snack on next. Finally, both cures are supposedly finished, and Bailey gets the Death One antivirus ready, but as she leaves, the worm-eyed zombie shows up and bites her arm, infecting her. She still manages to administer the antivirus to John, who collapses as the effects of the virus are slowly undone.
Reuniting with Ann, Kenny, Peter West, Peter, Francine, and Patricia, she receives a barrel with the cure for the zombie affliction from the island from Ann, who tells her that the cure is airborne and that all she might need to do is set the barrel on the ground and tap it hard enough, and a colorless smoke will envelop the island. Bailey tells Peter West that if the cure doesn't work and she becomes a zombie, he should kill her, burn her body in a funeral pyre, and scatter her ashes at sea.
She walks in the center of the zombie mob that had surrounded them, sets the barrel down, and taps it hard enough. The colorless smoke is sprayed all over the island, and when it clears, Bailey appears to be dead. A newly rehumanized John walks up to the group just as Bailey gets back up and realizes that the cure had worked after all. After they remember Bryan and free him from his bonds, he yells at them for not killing him when they had the chance. Bailey slaps him for being an ingrate and reminds him that at least he's back to normal. Susan Barrett, who had bitten Bryan after being bitten in the jugular, returns to the hut where Drs. Bolt and Menard worked, having recovered from the bite from the worm-eyed zombie, who then shows up and writes something in the dirt with a stick before departing. The word reads "GRACIAS".
Ann, Peter West, Bailey, John, Bryan, and Susan decide to continue their research on the zombie contagion so that the whole world will eventually be cured. The last shot is of the party outside the hut, breathing fresh and zombie-free air for the first time in years.
- Alfred Enoch as Peter
- Mila Kunis as Francine
- Rupert Grint as Ann Bolt
- Ewan McGregor as Peter West
- William Melling as Bryan Curt
- Keke Palmer as Susan Barrett
- Daniel Radcliffe as Kenny
- Chloe Grace Moretz as Patricia
- Emma Watson as Bailey Matheson
- Elio Germano as John
- Ottaviano Dell'acqua as the worm-eyed zombie