British animal rights activists break into a laboratory and are caught by a scientist while trying to free some chimpanzees being used for medical research. Despite the scientist's warnings that the chimps are infected with a disease (which he calls "Rage"), the activists let loose a chimp, which immediately attacks and infects the group.
28 days later, a bicycle courier named Jim awakens from a coma in a deserted hospital. As he leaves, he discovers London abandoned 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 and Mark, who rush him to their hideout. There they reveal that while Jim was comatose from his accident, a virus spread uncontrollably among the populace, turning most people into rabid, psychotic "Infected," resulting in societal collapse that possibly spread worldwide. Selena and Mark accompany Jim to his parents' house the next morning, where he discovers that they committed suicide. That night, two of the Infected attack the survivors, and when the fight ends Selena is forced to kill Mark after he reveals he had been cut and possibly exposed; she explains that the infection is spread through the blood and overwhelms its victims in seconds. After leaving, they discover two more survivors, Frank and his teenage daughter, Hannah, holed up in a block of flats, and are invited to spend the rest of the night.
Frank informs them the next day that supplies, particularly water, are dwindling, and plays them a pre-recorded radio broadcast transmitted by soldiers at a blockade near Manchester, who claim to have "the answer to infection." The survivors board Frank's cab in search of the signal source and during the trip bond with one another. When the four reach the deserted blockade, Frank is infected when a drop of blood from a dead body falls into his eye. Before succumbing he is killed by the arriving soldiers, who then take the remaining group to a fortified mansion under the command of Major Henry West. Jim quickly discovers that West's "answer to infection" involves waiting for the Infected to starve to death, and forcing female survivors into sexual slavery to rebuild the population. Jim attempts to escape with Selena and Hannah, but is captured by the soldiers, along with Sergeant Farrell, who disagrees with the Major's plan. During their imprisonment, Farrell theorizes to Jim that there is no worldwide epidemic, but rather that the island of Great Britain has been quarantined.
The next day, as two soldiers lead Jim and Farrell to execution, Selena and Hannah are being prepared for rape. Jim manages to escape while his escorts quarrel after killing Farrell, and notices the contrail of a jet aircraft flying high overhead, proving Farrell's theory. After luring West and one of his men to the blockade, Jim runs back to the soldiers' headquarters where he unleashes Mailer, an infected soldier that West kept chained outside for observation. Mailer attacks the soldiers in the mansion, while Jim sets out to rescue the girls, who had been split up in the chaos. Selena, held hostage by a surviving soldier, is then rescued by Jim, who arrives and savagely kills her captor. The two share a kiss, reunite with Hannah, and run to Frank's cab, only to encounter a vengeful West, who shoots Jim in the stomach. Hannah commandeers the cab and backs it up to the front door, where Mailer drags West out through the rear window and kills him. She then drives away with Jim and Selena.
Selena and Hannah rush Jim into a deserted hospital, where Selena performs life-saving emergency procedures. 28 days later, Jim is shown waking up in recovery again, this time at a remote cottage. Downstairs, he finds Selena sewing large swaths of fabric when Hannah appears. The three rush outside and unfurl a huge cloth banner, adding the final letter to the word "HELLO" laid out on the meadow. As a military jet flies over the landscape, the Infected are shown lying by the road, dying of starvation. After the jet zooms past the three waving survivors and their distress sign, Selena jokingly wonders if the plane saw them this time.