During the outbreak of the "Rage" virus, Don (Robert Carlyle) and his wife Alice (Catherine McCormack) live in a barricaded cottage they share with four others, somewhere in rural Great Britain. They let a terrified boy inside, and moments later, a pack of the Infected attack and enter the house. Alice refuses to leave without the boy; Don abandons Alice and escapes on a boat as the sole survivor.
Over the course of twenty-eight weeks following the original outbreak, the Infected have all starved to death and Britain has been declared relatively safe. An American-led NATO force, under the command of Brigadier General Stone (Idris Elba), begins repopulating the country. Amongst the new population are Tammy (Imogen Poots) and Andy (Mackintosh Muggleton), Don and Alice's children, who were in Spain during the initial outbreak. During their subsequent medical inspection, Major Scarlet Ross (Rose Byrne), chief medical officer of District One, notes Andy's differently coloured eyes, a trait inherited from his mother. They are subsequently admitted to District One, a heavily guarded safe zone of London on the Isle of Dogs guarded by the US Army. Sergeant Doyle (Jeremy Renner) and his friend, Flynn (Harold Perrineau), a helicopter pilot, are amongst the military presence charged with guarding District One. The children are reunited with their father who is now head caretaker of the district.
The next day the two children, wanting to find a photograph of their mother, slip out of the safe zone to return to their old home, where Andy discovers Alice, disheveled but alive. Andy and Tammy are recaptured by the US Army while Alice is decontaminated. A blood test reveals that she is infected with the Rage Virus but displaying few symptoms, labelling her an asymptomatic carrier. Using his all-access caretaker pass card to bypass security, Don makes an unauthorized visit to Alice in her isolation cell, and apologises for abandoning her at the cottage. When they kiss, the Rage Virus in her saliva immediately infects Don, who bites her and savagely gouges her eyes with his nails until she is dead. He goes on to attack and infect several soldiers in the building.
District One is put into Code Red Lockdown, and civilians are herded into safe rooms. Don breaks into a room with a huge crowd of several hundred and begins killing and infecting people, quickly causing a domino effect of attackers. Scarlet manages to rescue Tammy from containment but Andy temporarily gets separated from his sister. Soldiers surrounding the building are initially ordered to shoot only the Infected, but as the wave of infection grows, they are ordered to shoot all civilians. Doyle, unable to bring himself to comply with the order, abandons his post and escapes with Scarlet, the children, and others through the Greenwich foot tunnel. 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 may hold the key to a cure, and must be protected at all costs. Flynn arrives by helicopter to pick up Doyle, but refuses to take anyone else as they would be shot down if carrying possible infected persons.
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, breaking into an abandoned car to escape nerve gas released to kill the Infected. However, after the Infected are dead a group of soldiers, one of them carrying a flamethrower, are patrolling and nearing the car. The car will not start, so Doyle push starts the car before being incinerated by the flamethrower. Scarlet drives the car into the London Underground where she and the children continue on foot. In the darkness, Scarlet is ambushed and killed by Don. Don then attacks and bites Andy, but Tammy shoots Don before he can kill him. Andy remains symptom-free, but with darker, bloodier eyes like his mother. The children continue to Wembley 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 pass. Calls for help and screams can be heard over the radio of Flynn's now abandoned helicopter. A swarm of Infected are shown sprinting through a subway exit. As they run into the open, the Eiffel Tower comes into view, revealing that the Rage Virus has spread to France.