Years after a zombie apocalypse, survivors have set up outposts across the United States. One outpost in the city of Pittsburgh, Pennsylvania, contains a feudal-like government. Bordered on two sides by rivers and on the third by an electric fence, the city has become a sanctuary. The rich and powerful live in a luxury high-rise called Fiddler's Green, while the rest of the population subsists in squalor. Paul Kaufman (Dennis Hopper), the city's ruthless ruler, has sponsored Dead Reckoning, an armored personnel vehicle that can travel through the zombie-infested areas with ease.
Riley Denbo (Simon Baker) is the designer and commander of Dead Reckoning. Unlike Kaufman, Riley is respected for his work in protecting the citizens, as well as providing them with food and medical supplies. Using Dead Reckoning, Riley and his crew ventured into areas overrun with zombies to scavenge for supplies. On these mission, they notice many zombies exhibiting intelligent behavior. One such zombie is "Big Daddy" (Eugene Clark), formerly a gas station owner.
After the mission, Riley retires from commanding Dead Reckoning. Back to the city, he gets to Chihuahua (Phil Fondacaro)'s bar. There, he sees a hooker named Slack (Asia Argento) being forced in a cage with some zombies to entertain guests. Riley and Charlie (Robert Joy) save Slack; Charlie kills Chihuahua in the ensuing chaos. Riley, Charlie and Slack are arrested. Slack reveals that Kaufman ordered her execution, for helping Mulligan (Bruce McFee) to instigate rebellion among the poor.
Meanwhile, Cholo DeMora (John Leguizamo), Dead Reckoning's second in command, is denied an apartment in Fiddler's Green despite his service to Kaufman. In retaliation, Cholo takes over Dead Reckoning and threatens to destroy Fiddler's Green with it. Kaufman approaches Riley and tasks him, as well as Charlie and Slack, to retrieve Dead Reckoning. They are supervised by Manolete (Sasha Roiz), Motown (Krista Bridges), and Pillsbury (Pedro Miguel Arce).
On the way, Manolete is bitten and then killed by Slack. After catching up with Dead Reckoning, Riley approaches the vehicle alone. Charlie, Slack, and Pillsbury follow him after subduing Motown and leaving her behind. Realising Riley is working for Kaufman, Cholo holds both Riley and Charlie at gunpoint. As he prepares to fire Dead Reckoning's missiles at Fiddler's Green, Riley uses a small device and deactivates Dead Reckoning's weapons systems; he then destroys the device. Motown, who had regained consciousness, opens fire and nearly kills both Riley and Cholo (who is maimed by one of the gunshots). She is bitten by a zombie and killed by Slack. Riley convinces Cholo to allow him escape North and to join him, but the latter decides to head back to Fiddler's Green to deal with Kaufman; his partner, Foxy (Tony Nappo) accompanies him. While en route, Cholo is bitten by a zombie and leaves to kill Kaufman by himself. Riley takes over Dead Reckoning once again and returns to Fiddler's Green.
Elsewhere, Big Daddy (who had gathered a large group of zombies) learns that they can walk safely underwater. He leads the zombies to cross the river to the human city. They take the guards by surprise and begin massacring the people. As a result of the zombies making it into the city, the electric fences that once kept the zombies out have now become a wall to trap them and the humans inside. Seeing the city overrun, Kaufman runs with his money, and encounters a zombified Cholo in the parking garage. As the two struggle, Big Daddy kills both with a propane tank.
Riley's group arrives at the city only to come upon a drawbridge having already been drawn. Riley leaves to bring the bridge down, but a small group of zombies begin to attack Dead Reckoning. Riley and the others manage to dispose and evade the zombies. After crossing the bridge, they helplessly witness people being killed by the zombies. Realizing it is too late to save them, they mercy kill them with missiles. It is then revealed that most of the poor people were lead to safety by Mulligan, thus surviving the assault. Riley and Mulligan share a well-meaning goodbye as they split up with their groups. As they see Big Daddy and the zombies, who are, curiously, not attacking the surviving humans, leaving the city, Riley decides to leave them alone. While lighting up the rest of the fireworks (which were earlier used to distract the zombies but are now useless), Riley's group set off for Canada on Dead Reckoning.