The film takes place within a post-apocalyptic America, wherein a zombie apocalypse has occurred triggered by a virulent form of human adapted mad cow disease.
College student Columbus (Jesse Eisenberg) is on his way to Columbus, Ohio to see if his parents are alive. He loses his car in an accident and encounters Tallahassee (Woody Harrelson). They travel together and when they stop at a grocery store, they meet two sisters, Wichita (Emma Stone) and Little Rock (Abigail Breslin). Through a con, the sisters manage to steal their weapons and truck. 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 Hummer, but Columbus proposes a truce.
Columbus tells Wichita he is heading home to Columbus, but she blurts out that Columbus, Ohio has been burned to the ground and is overrun by zombies. Columbus decides to not go home and stays 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. In Murray's home movie theater Columbus shows Little Rock Ghostbusters; when Murray enters in order to scare Columbus and Little Rock as a practical joke, Columbus shoots and kills him, thinking he is a zombie.
After a makeshift funeral, Tallahassee reveals he lost his son to the zombies; Wichita begins developing feelings for Columbus. Fearing attachment, Wichita leaves with Little Rock for Pacific Playland. Columbus decides to go after Wichita, and he and Tallahassee pursue the sisters in one of Murray's vehicles.
Wichita and Little Rock arrive at Pacific Playland and turn on all the rides and lights, attracting nearby zombies. A battle ensues, leaving the sisters trapped on a drop tower ride and running low on ammunition. Tallahassee and Columbus arrive just as the sisters' ammunition is depleted. Tallahassee manages to lure the majority away, then intentionally locks himself in a game booth while Columbus goes after the sisters. Columbus save the girls and in thanks, Wichita reveals her real name (Krysta) to him. The two share their first kiss. Tallahassee eliminates the remaining zombies single-handedly. Columbus comes to the realization that this is the only family he needs, and the four leave Pacific Playland together