Ana (Sarah Polley), a nurse, finishes a long shift at her Milwaukee County hospital and returns to her peaceful suburban home.
She and her waiting husband Louis (Justin Louis) make love and go to sleep, missing warnings beginning to trickle through the local media concerning a mysterious and rapidly-spreading contagion which turns its infected hosts into reanimated flesh-eating ghouls.
The next morning they are awoken by their zombified neighbor, a young girl, who bites Louis in the throat.
Ana locks the zombie out of the room, but despite her frantic efforts, Louis dies, immediately reanimates as a zombie, and chases Ana into the bathroom.
Ana escapes out the window and flees from her now chaos-torn neighborhood in her car, before a failed hijacking attempt sends her crashing into a tree. The opening credits roll, showing the worldwide collapse of human civilization.
Ana meets Kenneth (Ving Rhames), a grim police sergeant traveling to Fort Pastor, a nearby US Army base. With the route to the base blocked by zombies, they join three others - jack-of-all-trades Michael (Jake Weber), petty criminal Andre (Mekhi Phifer) and his pregnant Russian wife Luda (Inna Korobkina).
The five survivors break into the nearby Crossroads Shopping Mall.
Inside the mall, a scuffle with a zombified mall security guard results in Luda getting a minor bite-wound and Kenneth getting a cut on his arm.
They confront three living security guards - C.J. (Michael Kelly), Bart (Michael Barry) and Terry (Kevin Zegers) - and give up their weapons in exchange for refuge. After the group secures the mall, they head up to the mall's roof to dispose of bodies and paint SOS signs.