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.
Meanwhile, Andre, faced with the fact that Luda's wound is inexorably killing her, sinks into denial and has Luda tied to a bed. Even as she gives birth, she dies and reanimates. Norma checks on the couple, discovering the zombie-Luda and the deranged Andre. Norma shoots Luda in the head, causing Andre to snap completely; they exchange more gunfire, killing each other. Ana arrives and opens the bundle Andre was clutching to reveal a zombie baby. She pulls her revolver and a single shot rings through the mall.The remaining survivors decide to flee the mall, fight their way to the local marina, and from there travel out on Steve's yacht to an island in Lake Michigan. They reinforce two shuttle buses from the parking garage, while chainsaws, propane tanks and other supplies are loaded on board. Meanwhile, Andy is starving, so the mall survivors strap a pack of food on "Chips", the dog from the basement, and lower him into the parking lot. Chips reaches the gun-shop untouched, but a zombie gets in as well and badly injures Andy. Nicole, distraught over Chips, takes the delivery truck and barges into the gun store, where she is trapped by a now-zombified Andy.A team led by Kenneth head into the sewers. They reach the gun store, kill the zombified Andy, find Nicole and Chips, and stock up on weapons and ammunition. They escape back to the sewers, but the zombies pursue them, kill Tucker, and, thanks to assigned guard Steve's negligence, break into the mall, forcing an immediate evacuation. The survivors pile into the buses and smash out into the parking lot, where a propane bomb is used to clear a path through the waiting horde. When a zombie clings to the side of Kenneth's bus, Glen decides to use a chainsaw to saw him off. After a huge turn, Glen loses control of the chainsaw and he accidentally cuts Monica in half. Blood splatters on the windshield causing Kenneth to crash the bus. Steve flees the toppled bus and is attacked by a hitchhiking zombie.
The others scramble for the second bus, meeting zombie-Steve on the way. Ana kills him after discovering both Glen and Monica's dead bodies in the crash. She then lingers to get the boat keys off his corpse, allowing more zombies to catch up with them. Ana flees to the bus, and Michael helps her in. After a struggle, they pull away and speed to the marina, where they crash the bus and dash for the boat. C.J., cornered in the bus, detonates a final propane tank, blowing up the vehicle, more zombies, and himself. The remainder of the group gets on the boat, except for Michael, who was bitten while helping Ana. Ana watches as Michael draws his pistol, places it under his chin, and pulls the trigger leaving Ana, Kenneth, Nicole, Terry and Chips as the only survivors.
The closing credits are interspersed with short clips from a camcorder found on the boat. The boat drifts to an island after the motor quits during the grim journey across the lake, where they are met by a new swarm of zombies. The film ends with the dropped camcorder recording dozens of zombies running towards the survivors in their now powerless boat.
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