Set in a post-apocalyptic future where zombies have overrun the world, the remaining humans are confined to a fortified city surrounded by rivers and electric fences. Inside the city, society is split between the wealthy elite who live in a luxurious skyscraper called Fiddler's Green, and the poor who live in the slums below.

A military group led by Riley Denbo (played by Simon Baker) and his reckless second-in-command Cholo DeMora (played by John Leguizamo) patrols the surrounding zombie-infested areas in a heavily armed vehicle called Dead Reckoning, scavenging supplies for the city.

Things escalate when Cholo, frustrated by being denied access to Fiddler's Green by its cruel ruler Paul Kaufman (played by Dennis Hopper), hijacks Dead Reckoning and threatens to attack the city. At the same time, the zombies—led by an unusually intelligent zombie known as Big Daddy—begin to evolve and organize, launching an unprecedented attack on the human stronghold.