Don (Robert Carlyle) and his wife Alice (Catherine McCormack) prepare dinner where they are living with an old couple and 2 other people that are the only survivors in a heavily reinforced cottage somewhere in rural, Rage virus–infected Britain. As they are taking their meal, they suddenly hear a young boy banging on the door begging to be let in. At first they argue not to open it due to the Rage virus' outbreak. Don opens the door to let the child inside, who says he is from Sandford and has been fleeing his parents who are now infected. Moments later, a pack of the infected discover the hideout and break in, 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, the infected have all starved to death and Britain is declared relatively safe again, allowing for re-population. The re-construction of Britain begins. The process proceeds throughout the weeks.

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 the very young, 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, Ross 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 unit 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. Inside their new penthouse, Don tearfully recounts his escape, saying that Alice was killed by the infected, but misrepresents the truth, saying that he witnessed Alice's death, to hide the fact that he fled and abandoned her to her fate.