Two months have passed since a strain of mad cow disease mutated into “mad person disease” that became “mad zombie disease”, which overran the entire United States (with the infection presumably spreading to the rest of the world), turning many Americans into vicious zombies. Survivors of the zombie epidemic have learned that growing attached to other survivors is not advisable because they could die at any moment, so many have taken to using their city of origin as nicknames.
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 does not appear to be sociable, Tallahassee reluctantly allows Columbus to travel with him. Tallahassee mentions he misses his puppy, “Buck” that was killed by zombies, as well as his affinity for Twinkies, which he actively tries to find.
The pair meets Wichita (Emma Stone) and her younger sister Little Rock (Abigail Breslin) in a grocery store. The sisters turn out to be con artists and trick Tallahassee and Columbus into handing over their weapons by pretending that Little Rock is infected by the disease, then stealing 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 saying 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 hometown 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 the mansion of Bill Murray. Tallahassee and Wichita meet Murray himself, uninfected but disguised as a zombie so he can walk safely around town. 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 “Buck” was not Tallahassee’s puppy, but his young son, who had become infected and died as a result. Wichita and Columbus become increasingly attracted to each other, 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 so they can enjoy the park, only to unwittingly draw the attention of several zombies in the surrounding area. A chase ensues, and just as the sisters are trapped on a drop tower ride, Tallahassee and Columbus arrive. Tallahassee lures the zombies away, creating a distraction for Columbus to get to the tower ride; both using 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 fear of clowns while facing off against a clown zombie. As a show of thanks, Wichita kisses Columbus and reveals her real name: Krista. As the group leaves Pacific Playland, Columbus realizes that without relating to other people, one might as well be a zombie and that he now has what he has always wanted—a family.