Two months have passed since a mutated strain of mad cow disease mutated into "mad person disease" that became "mad zombie disease" which overran the entire United States population, turning American people into vicious zombies. Unaffected college student Columbus (Jesse Eisenberg) is making his way from his college dorm in Austin, Texas, to Columbus, Ohio, to see whether his parents are still alive. He encounters Tallahassee (Woody Harrelson), another survivor, who is particularly violent in killing zombies. Though he doesn't appear to be sociable, Tallahassee reluctantly allows Columbus to travel with him. Tallahassee mentions he misses his puppy that was killed by zombies, as well as his affinity for Twinkies, which he actively tries to find. Survivors of the zombie epidemic have learned that it is best not to grow attached to other survivors, because they could die at any moment, so many have taken to using their city of origin as nicknames, i.e. Columbus is from Columbus, Ohio.
The pair meet Wichita (Emma Stone) and her younger sister Little Rock (Abigail Breslin) in a grocery store. The sisters are con artists, and trick Tallahassee and Columbus into handing over their weapons by pretending that Little Rock was infected by the disease, then steal their Escalade. The two men find a yellow Hummer H2 loaded with weapons and go after the sisters. However, the girls spring another trap for them and take them hostage. Tallahassee steals his gun back and has a stand-off with Wichita, until Columbus lashes out in anger that they have bigger problems to worry about, resulting in an uneasy truce between them. The sisters reveal that they are going to the Pacific Playland amusement park in Los Angeles, an area supposedly free of zombies. After learning his home town has been destroyed, and his parents likely killed, Columbus decides to accompany the others to California. Along the trip, Columbus persists in trying to impress and woo Wichita.
When the group reaches Hollywood, Tallahassee directs them to Bill Murray's mansion. Tallahassee and Wichita meet Murray himself, uninfected but disguised as a zombie so he can walk safely around town (and play golf). Murray is killed when Columbus shoots him, mistaking him for a real zombie during a practical joke while watching Ghostbusters with Little Rock. Columbus realizes during a game of Monopoly that Tallahassee has not been grieving for his puppy, but rather for his young son. Wichita becomes increasingly attracted to Columbus, and Tallahassee bonds with Little Rock, with whom he was previously at odds. Despite Wichita's attraction to Columbus, she fears attachment and leaves with Little Rock for Pacific Playland the next morning. Columbus decides to go after Wichita, and convinces Tallahassee to join him.
At Pacific Playland, the sisters activate all the rides and lights and begin to enjoy the park, but also unwittingly draw the attention of all the zombies in the surrounding area. A chase ensues, and just as the sisters are trapped on a drop tower ride called Blast Off, Tallahassee and Columbus arrive. Tallahassee lures the zombies away from the tower, creating a distraction for Columbus to get to the tower ride; both use the attractions to their advantage. Tallahassee eventually locks himself in a game booth, shooting zombies as they arrive. Columbus successfully evades and shoots through several zombies to reach the tower and help the girls down, but not before changing one of his rules for survival to conquer his coulrophobia by facing off against a clown zombie. In thanks, Wichita kisses Columbus and reveals her real name: Krista.
Tallahassee raids a deep fried Twinkies stand in search of his snack. During this Columbus is startled by the noises of a rat and accidentally shoots at the last remaining box of Twinkies in the pantry, destroying all the cakes and making them inedible. Luckly Little Rock has gotten a Twinkie beforehand and gives it to Tallahassee. The movie ends with the group leaving Pacific Playland as Columbus realises he now has what he's always wanted: a family.
Who lures the zombies away from the tower?
Tallahassee