The film takes place within a post-apocalyptic America, where a zombie apocalypse has been triggered when mad cow disease became mad human disease and then worse.

College student Columbus (Jesse Eisenberg) is on his way to Columbus, Ohio to see if his parents are still alive. He loses his car in an accident and encounters Tallahassee (Woody Harrelson) who is on a quest to find Twinkies. They travel together and when they stop at a grocery store, they meet two sisters, Wichita (Emma Stone) and Little Rock (Abigail Breslin). The sisters con them into handing over their weapons and steal their vehicle. The two men walk and soon find a Hummer H2 truck loaded with weapons. They then meet the girls again, who attempt to take the truck, their vehicle having broken down. Columbus proposes a truce and suggests they travel together.

Columbus tells Wichita he is heading home to Columbus, Ohio but she blurts out that it has been burned to the ground and is overrun by zombies. He decides instead to stay with the group. Wichita tells Columbus that she is taking Little Rock to "Pacific Playland" in Los Angeles, an amusement park rumored to be zombie-free.

On the way to the park, they pass through Hollywood and Tallahassee decides to take them to Bill Murray's mansion. Tallahassee and Wichita meet Murray himself, uninfected but disguised as a zombie with make-up so that he can walk safely among the infected and play golf without being bothered. Little Rock is unfamiliar with Bill Murray so Columbus shows her the film Ghostbusters. Murray later enters in order to scare Columbus and Little Rock as a practical joke, but thinking he is a real zombie Columbus shoots and kills him.
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