The film opens with reporter Angela Vidal (Jennifer Carpenter) and her cameraman Scott Percival (Steve Harris) doing a report on the night shift of a Los Angeles fire station. Angela and Scott are introduced to firefighters Fletcher (Johnathon Schaech) and Jake (Jay Hernandez), whom they will be following for the evening.
A medical emergency at an apartment complex is reported and the night shift is sent in. Yuri (Rade Serbedzija), the building manager, explains that a woman has been screaming, but is now silent. They are joined by two police officers, James (Andrew Fiscella) and Danny (Columbus Short), in the lobby. They are led to the apartment of Mrs. Espinoza (Jeannie Epper), the source of the screaming. Yuri unlocks the door when she does not answer, and a dog runs out. Within the apartment, Espinoza is struggling to breathe, covered in blood, and foaming at the mouth. She bites James before being subdued by Fletcher. The others take James downstairs to get medical assistance, but find the building sealed shut by the authorities. Fletcher falls from the top floor, bitten, breaking his leg. Lawrence (Greg Germann), a veterinarian, tends to the injured men.
Danny and Jake go upstairs to subdue Espinoza, where they find the cleaning lady dead in her apartment. Danny shoots Espinoza when she charges at them. They all return to the lobby, meeting Sadie (Dania Ramirez) on the way. By this time, all exterior windows and doors are being sealed, and cell phones are being jammed. Anyone who attempts to leave is forced back at gunpoint. Jake believes they are being quarantined due to a nuclear, biological, or chemical emergency. Danny and Jake round up the tenants and bring them to the lobby, including Elsie (Stacy Chbosky), who is displaying the same symptoms as Espinoza.
While Fletcher, James, and Elsie are treated by Lawrence, Angela begins interviewing tenants. One little girl, Briana (Joey King), is sick. Briana claims that she has a dog named Max who was sick and taken to an animal hospital. Lawrence states that the symptoms of those infected are similar to rabies, only much more fast-acting.
Angela and Scott notice Bernard and Sadie sneaking away, looking for a TV to try to discover what is happening outside. Espinoza's infected dog appears and attacks one of the tenants. They reach Bernard's apartment and turn on the news, where the chief of police claims that everyone has been evacuated from the building, just before the power is shut off. The group is then attacked by Elsie, whom Scott kills.
Downstairs, Fletcher tries to attack everyone in the lobby, but Danny injects him with a sedative and then rounds everyone up in the textile shop. Danny states that Centers for Disease Control and Prevention agents are coming in to give blood tests. The residents are also told that anyone who is not infected will be released. Lawrence observes that the only way to test for rabies is through a brain sample, not a blood test, but Danny insists on following procedure. After a roll call, Yuri reveals that the penthouse apartment of the building is being rented by a man from Boston who is absent.
The CDC agents arrive and examine the infected victims, taking a brain sample from Fletcher. Fletcher breaks his restraints and attacks one of the agents. Danny, Jake, and the other agent escape, leaving Lawrence locked in the room with the infected. The textile shop is locked and the surviving CDC agent is forced to explain the situation: Briana's dog was brought to a vet with an unknown illness and infected all the animals there. The dog was traced back to the apartment building; Briana's fever is then called into question, and she bites her mother before running upstairs. Briana's mother, who is now hysterical, is handcuffed to the stairwell.
Danny is bitten by Briana, and many of the survivors downstairs are bitten as well. The survivors lock themselves in an upstairs room. The surviving CDC agent has been bitten and runs away to keep from infecting the others. He is locked in an adjacent room while the others try to figure out what to do. Sadie is also bitten but Bernard pleads with the others not to kill her. Bernard cuts through a window seal to call for help, but is killed by a sniper. Yuri reveals that they can escape through a basement passage into the sewers; however, the keys are in his apartment. He is then killed by the infected agent. His wife is then killed by Sadie, who succumbed to the infection.
Angela, Scott, and Jake make their way to Yuri's apartment to get his keys, avoiding and killing several infected while doing so. Jake is bitten along the way, and the infected chase Angela and Scott into the penthouse apartment. Within, they discover that the man from Boston, who was renting the penthouse, was a member of a doomsday cult that was cultivating an "Armageddon virus". A noise from the attic prompts Scott to investigate, and he finds an infected boy. The boy destroys the light on Scott's camera, so he turns on the night vision. Angela and Scott then see an emaciated man (Doug Jones) emerge from another room. He walks past them initially but attacks Scott when Angela inadvertently makes a noise. Angela watches through the night vision of the camera as the infected man eats Scott. The man then attacks her, causing her to drop the camera. The final shot is of Angela crawling back to the camera only to be dragged into the darkness, screaming.
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