Ana, a nurse, finishes a long shift at her Milwaukee hospital, then returns to her peaceful suburban home and waiting husband Luis. The two jump in the shower and miss emergency broadcasts on TV about a mysterious epidemic. The next morning the couple is awakened by their neighbor\'s zombified daughter entering their room. She kills Luis, who immediately reanimates as a zombie. Ana flees in her car, but an attempted hijacking by a lone bus driver sends her crashing into a tree and knocks her out. Accompanying the opening credits, a bleak news-video montage depicts swarms of zombies overwhelming human civilization worldwide.
Upon awaking, Ana meets Kenneth, a police sergeant. They and three others – jack-of-all-trades Michael, petty criminal Andre and his pregnant Russian wife Luda – break into the nearby Crossroads Shopping Mall. Inside, a scuffle with a zombified mall security guard results in Luda getting a minor wound.
They confront three living security guards – C.J., Bart and Terry – and give up their weapons in exchange for refuge. After the group secures the mall, they head to the roof and \"meet\" another survivor, Andy, who is stranded alone in his gun store, across the mall\'s zombie-infested parking lot.
The next day, a delivery truck carrying survivors enters the mall\'s parking lot closely followed by zombies. Terry sides with the new arrivals, C.J. and Bart are disarmed, and the inhabitants of the delivery truck are allowed into the mall, among them the driver, Norma, Steve, Tucker, Frank (who has been bitten), his teen daughter Nicole, Monica, Glen and a bloated woman who is heavily infected. When, the bloated woman becomes a zombie and is killed by Ana, the group determines that the disease is blood-borne and bites are how the zombies multiply; after Ana and Michael argue about what to do with the rapidly-deteriorating Frank, the man is isolated in a store with Kenneth. Michael and Ana achieve an awkward reconciliation, which is interrupted by a zombie-like call from Frank, immediately followed by Kenneth\'s shotgun blast.
Though the mall provides many material distractions, and Michael and Ana edge towards a romance, the undead surround the refuge in ever-increasing numbers, eventually filling the parking lot. The mall’s power goes out and C.J., Bart, Michael and Kenneth enter the underground parking garage to turn on the emergency generator. After they meet an unaffected dog, a zombie swarm kills Bart and traps the others in the generator compartment, where they douse the zombies with gasoline and set them ablaze.