Don (Robert Carlyle) and his wife Alice (Catherine McCormack) prepare dinner in the heavily-reinforced cottage they share with four others, somewhere in rural Great Britain. During their meal a boy bangs on the door, begging to be let in. After arguing amongst themselves Don lets the child inside, who says he is from Sandford and has been fleeing his infected parents. Moments later, a pack of the infected attack and enter the house, quickly overwhelming the group. Alice refuses to leave without the boy; Don abandons Alice and escapes in a boat, emerging as the sole survivor.


Over the course of 28 weeks following the original outbreak, the infected have all starved to death, Britain has been declared relatively safe, and re-population has begun.


An American-led NATO force, under the command of Brigadier General Stone (Idris Elba), begins repopulating the country with both old and new residents. The chief medical officer of District 1, Major Scarlet Ross (Rose Byrne), is surprised by the inclusion of adolescents and children, amongst whom are Tammy (Imogen Poots) and Andy (Mackintosh Muggleton), Don and Alice's children who were in Spain during the initial outbreak.


At 12 years old, Andy is the youngest person in Britain, and during their subsequent medical inspection, Scarlet notes Andy's heterochromia, a trait he inherited from his mother. Andy and Tammy are subsequently admitted to District 1, a heavily-reinforced, fully functional section of London on the Isle of Dogs guarded by the United States Army, including a detachment from Delta acting as a rooftop observation team. With them are a sergeant, Doyle (Jeremy Renner), and an observation helicopter pilot, Flynn (Harold Perrineau). The children are reunited with their father Don, who is now head caretaker of the district. Don tearfully recounts his escape to them, saying that Alice was killed by the infected, but states that he witnessed Alice's death to hide the fact that he abandoned her.


The next day the two children 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, labeling her an asymptomatic carrier, as evidenced by her blood-shot eye. Though Scarlet wants to keep Alice alive to seek a possible vaccine or cure, she is overruled by Stone, who wants Alice killed to prevent a possible further outbreak of Rage.