Months later, Alice travels to Alaska in an airplane, tracking broadcasts from a safe haven called Arcadia; however, she only finds abandoned planes, and is attacked by feral Claire Redfield (Ali Larter). Alice destroys a spider-like device on Claire's chest, giving her amnesia and pacifying her. They travel to the ruins of L.A., where they find survivors living in a prison surrounded by infected. They meet Luther West (Boris Kodjoe), Wendell (Fulvio Cecere), Crystal Waters (Kacey Barnfield), Bennett (Kim Coates), Kim Yong (Norman Yeung), and Angel Ortiz (Sergio Peris-Mencheta). With their help, Alice lands on the prison's roof and learns Arcadia isn't a fixed place, but a cargo tanker traveling along the coast. However, though the ship hasn't moved, no-one from it has responded to the group's rescue flares. Luther takes Alice to the last inmate, Chris (Wentworth Miller), who insists he's falsely imprisoned, and will reveal an escape route for freedom. Alice goes to the showers to wash up, but catches Wendell attempting to peep. They are attacked by a group of infected that dug into the prison, and take Wendell; she manages to kill them.
Desperate, they free Chris, who reveals Claire's his sister, and the prison has an armored car they can use to escape. However, a giant axe-wielding monster begins breaking down the gate. Alice, Chris and Crystal go to the basement armory to get more guns; however, zombies kill Crystal en route. Luther and Claire reinforce the gate. Angel informs Bennett and Yong the car is missing its engine and it would take a week to fix. Bennett shoots Angel and heads for Arcadia in Alice's airplane. The Axeman breaks down the gate, allowing the zombies into the prison. The group decides to use the zombie-dug tunnels to escape into the sewers. Yong is slashed in half by the Axeman, whom Alice and Claire kill. Unfortunately, Luther is dragged back into the tunnels by a zombie. Alice and the Redfields board the Arcadia, discovering it functional but abandoned. Claire then remembers Arcadia is an Umbrella trap to get test subjects; they release the survivors, among them K-Mart (Spencer Locke). Alice follows a trail of blood deeper into the ship, where she finds Wesker. The T-virus revived him, but it battles Wesker for control, something he believes fresh human DNA can pacify; the Umbrella staff fled when he began eating test subjects. Alice's DNA is superior to his, since she retained control despite bonding with the virus at a cellular level; he believes eating her will give him back control.
The Redfields fight Wesker while Alice battles Bennett, now working for Wesker. Wesker easily overpowers Chris and Claire, but Alice is able to defeat both Bennett and Wesker with help from K-Mart. They lock Bennett in the room with Wesker's corpse. Bennett is devoured by Wesker when he revives. Wesker then escapes in an aircraft, activating a bomb on the Arcadia; the plane explodes instead as Alice placed the bomb there beforehand. Unbeknownst to them, Wesker parachutes away from the explosion, while Luther emerges from the sewers, battered but alive. Alice resolves to turn Arcadia into a real haven and broadcasts a new message for any other survivors. As Alice, Claire and Chris watch over from Arcadia, it is approached by a military squadron of Umbrella aircraft.
During the post-credits scene in one of the aircraft, Jill Valentine (Sienna Guillory), who went missing after Resident Evil: Apocalypse, is dictating the attack wearing the same mind control device used on Claire.