Zone One follows protagonist Mark Spitz as he struggles to survive in the aftermath of a plague that has turned the vast majority of the population into zombified "skels" and "stragglers. Told over a three-day period–with frequent flashbacks to Mark's life before the plague and in the early days following–the plot follows Mark as he works as a "sweeper" tasked with killing the remaining skels and stragglers in a fortified area of Manhattan named Zone One. Mark is joined in this endeavor by two other survivors named Kaitlyn and Gary, and together three form the Omega Unit.
At the beginning of the novel, Mark is nearly killed by a group of four skels who had been trapped in a locked room of an office building. Thankfully, Mark is rescued by Gary, and the Omega Unit continues on its mission. In an extended flashback sequence, it is revealed that Mark was at a casino with his friend Kyle when the plague broke out. So consumed by their gambling, Mark and Kyle fail to realize that the plague is spreading rapidly. When Mark returns home after the end of the gambling binge, he finds his mother bent over his father "gnawing away with ecstatic fervor on a flap of his intestines" in what becomes known as the Last Night before the total collapse of society. As a result of this experience, Mark, like most of the survivors, struggles with PASD, or Post-Apocalyptic Stress Disorder. While PASD has a variety of symptoms, Mark is afflicted most acutely with frequent nightmares.
The following day, a Saturday, the Omega Unit bumps into another team, the Bravo Unit, while on duty. They soon discover that they've been assigned the exact same area to clear of skels, a situation that is not supposed to happen. This is the first indication that things are starting to go awry in Zone One and with the new government established in the city of Buffalo. The narrative then transitions into another flashback sequence, describing Mark's relationship with Miriam Cohen Levy, or Mim. After surviving on his own for several weeks after the collapse, Mark meets Mim in a toy store. The two immediately become close and develop a romantic relationship. When they exchange stories about their lives, Mim reveals that she was the mother of three children who all perished in the plague along with Mim's husband Harry.
The narrative then transitions back to the present, in which Mark wanders around "the new kingdom of Zone One" (p. 161). The narrative quickly transitions into another flashback in order to explain how Mark Spitz received that nickname (his birth name is never referenced). It is revealed that before coming to Zone One, Mark had worked on a crew of "wreckers" tasked with clearing cars off the I-95 highway in Connecticut. One day, a member of the crew opens the back door to a semi-truck that is stuck on a bridge, and a horde of skels bursts out. While the rest of the team jumps from the bridge down to the water below, Mark admits that he cannot swim and doesn't jump. He's then christened with the nickname Mark Spitz after the famous American Olympic swimmer of the same name.
The following flashback describes Mark's experience at a farmhouse in Northampton, Massachusetts. There, he meets Jerry, Tad, and Margie who have been hiding out in the house. While they are initially reluctant to let him in, Margie insists, and the four develop a strong bond. Unfortunately, a group of skels begins to gather around the house. Unable to leave the house for several days, Margie panics and begins attacking the skels. Alerted to the presence of humans inside the house, the skels begin attacking. While trying to escape, Jerry falls and is eaten by the skels. A group of soldiers fortunately come and rescue Mark.
Returning to the present of the novel, news reaches Zone One that some of the other settlement camps have begun to fall to onslaughts of skels. The narrative then transitions back to the story of Mark and Mim's relationship. After living in the toy store for several months, and falling deeply in love, Mim goes missing one day. Mark tries to find her but is unsuccessful.
On the final day, a Sunday, Gary is bitten by a skel. As Mark rushes back to the headquarters of Zone One to get supplies, the wall surrounding the fortress falls and skels begin to flood in. Mark then tries to escape in a truck with several other survivors. Feeling a sense of obligation to Kaitlyn, Mark jumps out of the truck near the fortune teller's where he finds Gary's body–knowing that he had been infected by the plague, Gary had taken his own life. As skels swarm all around, Mark is unable to find Kaitlyn. In the final sentence of the novel, Mark walks out into the swarm. His fate, and the fate of society at large, is left unknown.
