The movie begins in Leadville, Colorado. Trevor (Michael Welch) and his girlfriend, Nina (AnnaLynne McCord), are in an abandoned building with two of their friends having a romantic encounter. They leave the building to go back to their respective parents' houses. They see a long line of cars at a military roadblock sealing off the city. An angry man yells at the officers to let him through as his child is sick and needs medical care, and we learn that there has been an outbreak of some sort as medical help is needed throughout the town. They are introduced to Captain Rhodes (Ving Rhames) and Corporal Sarah Cross (Mena Suvari). Soon after, privates Bud Cryinside (Stark Sands) and Salazar (Nick Cannon) show up. Cross takes Bud to go and visit her mother, who has become sick. She arrives home, talks to her brother (Trevor), checks on her mother, then goes to the house of one of Trevor's friends, Kyle, after Trevor and Nina explain his symptoms as being similar to their mother's.

When Bud and Sarah arrive at Kyle's house, they find the bodies of his parents, which appear to have been mauled and bitten by an animal and were stashed behind a curtain. Kyle is nowhere to be found. They radio Captain Rhodes and take Nina, Trevor, and Trevor's mom to the local hospital. There, Sarah talks to Dr. Logan (Matt Rippy) at the urging of Rhodes, while out in the waiting room all the infected have suddenly gone frozen. Bud runs to inform Sarah of the situation, when all the infected reanimate. They turn into zombie-like creatures, although unlike traditional zombies they were never dead to begin with, and possess super-human strength that allows them to run, jump long distances, and crawl on the ceiling. Nina and Trevor escape and run to the radio station while Sarah, Salazar, and Bud become trapped in an upstairs room in the hospital. After dispatching Rhodes (who was infected), the three of them (Bud now infected due to a bite from Rhodes) make a stop at the gun store then go and rescue Trevor and Nina from the radio station.

The group heads to the abandoned warehouse from the beginning of the film. Bud has turned into a zombie, but is somehow able to think and does not attack his friends. The fact that Bud was a vegetarian is given by Sarah as a reason Bud didn't attack them (a vague similarity to Bub from the original Day of the Dead). The group descend into an underground bunker, where they reunite with Dr. Logan. They learn about a government project directed by Dr. Engel (Pat Kilbane). Bud tries to defend Sarah with his pistol and was able to shoot one of the zombies attacking her. Engel and a group of zombies kill Bud. Salazar is eaten by a group of zombies as Sarah runs to Trevor and Nina to burn all the zombies using gas tanks which are used as rocket boosters. They escape and as they drive off and the movie ends with a surviving zombie jumping in front of the camera in screamer fashion.