The Walking Dead occurs simultaneously with the events from the original comic series, where a zombie apocalypse overwhelms much of society. On day one of the outbreak, convicted criminal Lee Everett (voiced by Dave Fennoy) is being transported to prison when the police car crashes after hitting a walker. After killing the reanimated cop, Lee flees from a group of walkers and takes shelter in a suburban home, where he meets Clementine (Melissa Hutchison), a young girl whose parents had traveled to Savannah.

They are rescued by Shawn Greene (Peter Edward Mussad), who takes them to his father Hershel’s (Chuck Kourouklis) farm, where they meet Kenny (Gavin Hammon), his wife Katjaa (Cissy Jones), and their son Duck (Max Kaufman). After Shawn is killed by walkers, Hershel forces the group to leave. They travel to Macon, Lee's hometown, and join another group led by Lilly (Nicki Rapp), barricaded in Lee's family pharmacy.

The group includes Glenn (Nick Herman), who eventually leaves to find friends in Atlanta. Three months later, the group has holed up in a nearby motel and is low on supplies. They encounter a group of survivors, including Ben Paul (Trevor Hoffman), whose teacher's death teaches the group that everyone is already infected, turning into walkers upon death, regardless of being bitten. They make a deal with the St. Johns, a family running a nearby dairy farm, to exchange gasoline for food. However, they discover the St. Johns partake in cannibalism.

The group loses two of their own, including Lilly's father Larry (Terry McGovern), but eventually escapes the farm, leaving it overrun by walkers. On their way back to the motel, they find an abandoned car full of supplies and take what they need. Later, bandits attack the motel, drawing a horde of walkers. The group escapes, but Duck is bitten. Lilly, mentally unstable after losing her father, kills one of the group members and leaves the group. The remaining survivors head to Savannah by train, planning to find a boat to escape the mainland.

Along the way, they meet Chuck (Roger Jackson), a homeless survivor who advises Lee to teach Clementine how to defend herself. En route to Savannah, Duck succumbs to his bite, and in turn, Katjaa commits suicide. Near Savannah, the group meets Omid (Owen Thomas) and Christa (Mara Junot), a couple who joins them. A walkie-talkie that Clementine carries suddenly activates, with a man claiming he has her parents in Savannah. In Savannah, the group sets up shelter in an abandoned mansion but loses Chuck to walkers.

Lee and Kenny discover that all the boats in the area are either gone or destroyed, and that the walled community of Crawford has scavenged most of the supplies. Separated from the group, Lee encounters another group led by Vernon (Butch Engle), who helps him return to the mansion, where they discover a motorboat in a shed. The group raids Crawford for supplies, only to find the community overrun by walkers. They manage to escape, but not without losses.

Vernon leaves, doubting Lee's ability to protect Clementine. Clementine, desperate to find her parents, goes missing. In his haste to find her, Lee is bitten by a walker. Realizing he doesn't have much time left, Lee tries to find Vernon's group but discovers they have stolen the boat. Clementine contacts Lee via walkie-talkie, telling him that she is being held at a downtown hotel, the same one where her parents had stayed. Lee's group heads to the hotel, navigating rooftops to avoid walkers in the streets. Kenny is seemingly lost after sacrificing himself to save another member. Separated from Omid and Christa, Lee reaches the hotel alone and confronts Clementine's captor, The Stranger (Anthony Lam), who reveals he is the owner of the car they had previously ransacked.

After killing him, Lee and Clementine cover themselves in walker guts to avoid detection and head through the streets. They encounter Clementine's zombified parents, and a weakening Lee helps her reach an abandoned store. Inside, Lee urges Clementine to escape the city and find Omid and Christa. He instructs her to either shoot him or leave him to become a walker. In a post-credits scene, Clementine, having escaped the city, spots two figures in the distance who notice her.