An unknown virus has spread across the world, transforming nearly everyone into “skels,” flesh-craving zombies who transfer their condition to others by bite or scratch. Of the few human survivors is Mark Spitz, a young man who decides to volunteer as a sweeper, part of a civilian taskforce responsible for killing and disposing of remaining hostile skels and stragglers (their less violent counterparts) whom the marines have failed to clear out during their first sweep of the area. Mark is assigned to Fort Wonton, a fortified military base in New York City’s Chinatown, where he joins fellow civilians, Gary and Kaitlyn, as a part of team Omega. Omega is tasked with making their way through Zone One, the area that was once New York City’s Manhattan, clearing the area of stragglers so that one day the city may be inhabitable again.

Zone One takes place over the course of three days (Friday, Saturday, and Sunday), leading up to the eventual total takeover of Zone One by the virus. While the novel is primarily told in real time, Mark’s flashbacks are interspersed throughout the narrative. For instance, Mark recalls finding his infected mother feasting on his father’s entrails. He also tells of the various human settlements in Connecticut and Massachusetts that he joined briefly during the early days of the virus. He manages to barely escape to safety and is eventually rescued by the U.S. military. He also reflects on his early encounters with skels as a recruit at Fort Wonton, especially through the eccentric mentorship by his superior, the Lieutenant. As the end grows near, Mark reveals more of his sentimental past and hope for the future.

During the three days, team Omega continue their sweeps of Zone One. When they encounter another team in their area, they attempt to contact Fort Wonton to find out why their duties have overlapped. Mark finds out that the Lieutenant has committed suicide and that Bubbling Brooks, a renowned stronghold, has been destroyed by skels. Despite these disasters, officials from the main military headquarters in Buffalo attempt to maintain a hopeful public face, promising that Zone One will be ready for rebuilding soon.

On the last day, Omega is patrolling the area when Gary is suddenly attacked by a straggler. Mark notices the cunning speed of this particular straggler and puts this information together with his recollections of other advancing skels from his past. He determines that the skels are evolving into more intelligent forms. Upon returning to Fort Wonton to get help for his team, he realizes that the base is being swarmed by hundreds of skels. He escapes in a truck with the remaining officials, learning from the survivors that there is never going to be a summit and that reconstruction may not be possible. He leaves the truck to go find his team when he encounters many skels amassing on the street. He has no choice but to fight his way through the crowd. In the novel’s final scene, he descends into the mass gathering of skels.