After a devastating outbreak where mad cow disease mutated into a rabid infection known as "mad zombie disease," the United States is overrun with vicious zombies. Two months later, the remnants of civilization face a harsh new reality where forming attachments can lead to heartache and death. Thus, many survivors opt for using their hometown as their new identity.
One such survivor is Columbus, a college student who is making his way from his residence in Austin, Texas, to Columbus, Ohio, in search of his parents. Quirky and rule-oriented, he adheres to a strict set of survival guidelines that have kept him alive amidst chaos. Along his journey, he encounters Tallahassee, a violent yet resourceful survivor who enjoys taking down zombies with flair. Although he initially comes off as less than friendly, Tallahassee begrudgingly permits Columbus to accompany him on his quest. Their dynamic becomes further complicated as Tallahassee reveals his sentimental recollections of a pet puppy named “Buck,” tragically taken from him by the undead, and his relentless quest for Twinkies amidst the ruins.
Their journey leads them to a grocery store where they meet Wichita and her younger sister, Little Rock. The sisters, however, are not what they seem. They cleverly con Columbus and Tallahassee into relinquishing their weapons by staging a fake infection scenario with Little Rock, then making off with their vehicle. Once the duo regains their composure, they set out to reclaim their stolen ride, only to fall into another trap set by the sisters who now hold them hostage. An unexpected yet tense situation arises, but shared concern for survival allows them to forge a temporary alliance.
The sisters share their plans to travel to Pacific Playland, a supposedly zombie-free amusement park in Los Angeles. After discovering that his hometown has been destroyed and that he may have lost his parents, Columbus commits to joining the sisters on their road trip, all while attempting to woo Wichita.
Upon reaching Hollywood, the group decides to stop at the mansion of the famed Bill Murray, who hilariously disguises himself as a zombie to roam the streets safely. However, fate has other plans, and a practical joke leads Columbus to accidentally shoot Murray, mistaking him for an actual zombie. Tension mounts as Columbus learns the heartbreaking truth about Tallahassee's lost "Buck."
As feelings grow between Columbus and Wichita, their budding romance is complicated by her fear of emotional connection. When Wichita and Little Rock sneak away the next morning, Columbus is determined to pursue them, enlisting Tallahassee’s help.
At Pacific Playland, the sisters unwittingly draw a massive horde of zombies by activating the park's rides. In a thrilling sequence, Tallahassee and Columbus utilize their surroundings to save the sisters from imminent danger. Columbus even faces his longtime fear of clowns to rescue them, transforming one of his survival rules to "Be a hero."
As the dust settles, Wichita surprises Columbus with a kiss, revealing her real name—Krista. Leaving the amusement park behind, Columbus comes to an epiphany: to truly live, one must connect with others, leading him to realize through their harrowing journey, they have formed the family he had long desired.
Amidst the humor and zombies, Columbus’ journey includes a running gag of survival rules, evolving from "Cardio" to "Double tap," reflecting their experiences in a world turned upside down, capturing the spirit and absurdity of survival in the face of overwhelming odds.
