Late one night, British animal rights activists break into the Cambridge Primate Research Facility to free chimpanzees being used for medical research. The local scientist warns the activists that the chimps are infected with something he only calls "Rage", but the activists disregard him and set a chimp free. It immediately attacks and infects the activists and scientist.


Twenty-eight days later, a bicycle courier named Jim (Cillian Murphy) awakens from a coma in the deserted St Thomas' Hospital. As he leaves the hospital, he discovers London is completely deserted and rife with signs of catastrophe. Jim is soon discovered and chased through the streets by infected people before being rescued by two survivors, Selena (Naomie Harris) and Mark (Noah Huntley), who rush him to their hideout in the London Underground. They reveal that while Jim was comatose, the virus spread uncontrollably among the populace, turning most people into mindless, vicious creatures ("the Infected") and resulting in societal collapse, possibly on a global scale.


Selena and Mark accompany Jim to his parents' house, where he discovers that they committed suicide. That night, two of the Infected attack the survivors, and when the fight ends they discover that Mark is bleeding and is likely infected. Selena immediately kills him with a machete, explaining to Jim that the infection is spread through the blood and overwhelms its victims in seconds, rendering them deadly to others. She warns that should he become infected, she will kill him "in a heartbeat". As the two journey through the derelict city the next day, Selena rules out intimacy between her and Jim, declaring that only the fight for survival remains. They discover two more survivors, Frank (Brendan Gleeson) and his teenage daughter Hannah (Megan Burns), holed up in an abandoned block of flats. Invited to spend the night, Selena and Jim privately debate whether they should remain with Frank and Hannah. Jim says they seem like good people, while Selena fears they will slow her down, warning Jim that putting others ahead of one's own personal survival is a sure way to get killed.


The next morning, Frank informs Jim and Selena that supplies, particularly water, are dwindling, and plays them a prerecorded radio broadcast loop transmitted by soldiers near Manchester who claim to have "the answer to infection". The survivors board Frank's cab in search of the blockade and during the trip bond with one another. Selena's steely resolve begins to soften, while Jim's experiences on the trip begin to toughen him up. When the four reach the deserted blockade, Frank is infected by blood dripping from a corpse and is shot dead by hidden soldiers, who then commandeer the cab and take Selena, Jim and Hannah to a fortified mansion under the command of Major Henry West (Christopher Eccleston). As Hannah grieves, Selena and Jim reach out to each other romantically. Jim discovers that West's "answer to infection" involves waiting for the Infected to starve to death, while giving hope for community survival by forcing sexual servitude on the female survivors. Jim attempts to escape with Selena and Hannah, but is captured by the soldiers, along with Sergeant Farrell (Stuart McQuarrie), who disagrees with the Major's plan. While Jim and Farrell are imprisoned for the night, Farrell informs Jim that there is no worldwide epidemic, but rather that the island of Great Britain has been quarantined.