During the original outbreak of the Rage Virus, Don, his wife Alice, and four other survivors are hiding in a barricaded cottage on the outskirts of London. They hear a terrified boy pounding at their door, and they let him in. A few minutes later, they find that the Infected have followed the boy to them. The Infected attack and kill most of the survivors, while Don, Alice, and the boy are chased upstairs. Don is separated from Alice and the boy by the Infected and jumps out of a window, abandoning them. Don desperately sprints to a nearby motorboat and narrowly escapes.
After five weeks, all the Infected have died of starvation. After eleven weeks, NATO forces headed by the United States take control of Great Britain. After eighteen weeks, the island is declared relatively safe, although still under quarantine. Twenty-eight weeks after the outbreak, an American-led force, under the command of Brigadier General Stone, bring in settlers to re-populate the area. Among the new arrivals are Tammy and Andy, Don and Alice's children, who were in Spain on a school trip during the initial outbreak. They are subsequently admitted to District One, a safe zone guarded by the U.S. Army, on the Isle of Dogs. As they are examined by Major Scarlet Levy, the District's Chief Medical Officer, she notes Andy's differently coloured eyes, a trait inherited from his mother. Sergeant Doyle, a Delta sniper and his friend, Chief Flynn, a helicopter pilot, are amongst the military presence charged with guarding the District. Tammy and Andy are reunited with their father, who, having survived the original infection, was found by the U.S. army and has become the District's caretaker. In their new flat, Don explains what happened to him and their mother and that after escaping, he arrived at a military camp and survived by waiting for the Infected to die of starvation.
That night, Andy has a dream about forgetting his mother's face, so Tammy and Andy decide to visit their home to get a picture of her. The next day, they sneak out of the safe zone and proceed on a scooter through the depopulated London wasteland to their former home. To their shock, they find their mother alive, in a semi-conscious state. Doyle sees Tammy and Andy leave the safe zone, and they and their mother are quickly picked up by soldiers and returned to the district. Alice is taken to a quarantine room where she is tested and found to be an asymptomatic carrier of the Rage virus. While she does not show the uncontrollable rage, she is still extremely infectious. Don sneaks through the Security and makes an unauthorised visit to Alice in her isolation cell, begging her to forgive him. However, when they kiss the Rage Virus in her saliva immediately infects Don, who savagely kills her before going on a rampage, killing and infecting several soldiers in the building.
General Stone orders the building to be quarantined and District One to be put into Code Red Lock-down. Civilians are herded into safe rooms, but despite the precautions, Don breaks into a room containing a large crowd and begins killing and infecting them, quickly causing a domino effect of attackers. Scarlet rescues Tammy and Andy from containment as the soldiers in District One are ordered to shoot indiscriminately after being unable to differentiate between infected and uninfected persons during the panic. Doyle, unable to bring himself to comply with the order, abandons his post and escapes with Scarlet, Tammy, Andy, and others through the Greenwich foot tunnel. General Stone then orders that District One be firebombed; but large numbers of the Infected, including Don, escape the bombardment. Scarlet informs Doyle that the children might hold the key to a cure and must be protected at all costs. Flynn arrives by helicopter to pick up Doyle, but he refuses to take anyone else as they would be shot down for carrying possibly infected people.
Flynn contacts Doyle by radio and tells him to head to Wembley Stadium, but to leave the civilians. Doyle ignores his instructions and begins escorting the civilians to Wembley. He breaks into an abandoned car to escape nerve gas released to kill the Infected, but is burned alive by soldiers as he tries to push start the car. Scarlet drives the car away, as an Apache gunship tries to destroy the car. But all three manage to escape the chopper. She drives them into the London Underground where the trio continues on foot. Scarlet is ambushed and killed by Don who then attacks and bites Andy. Tammy shoots Don before he can kill Andy who remains symptom-free, but whose eyes are red like those of his mother, signifying that he is now an unknowing carrier of the Rage virus. They continue to the Stadium and are picked up by a reluctant Flynn, who flies them across the English Channel to France, as previously instructed by Doyle.
Twenty-eight days later, a French-accented voice requesting help is heard from the radio in Flynn's abandoned helicopter. A group of the Infected are seen running through a tunnel which, as they emerge into the open, is revealed to be the exit of the Paris Métro Trocadéro station with a view of the nearby Eiffel Tower.