One year after the events of Extinction, Alice (Milla Jovovich) and her clones lead the assault to attack Umbrella HQ, located in Tokyo, slaying the entire branch except for Albert Wesker (Shawn Roberts), who escapes in a tiltrotor plane and detonates a bomb that leaves a massive sinkhole. The real Alice boarded beforehand and attempts to execute Wesker, only for him to inject her with an anti-virus to remove her superhuman abilities. Wesker is revealed to have used the T-Virus to gain his own superhuman abilities and prepares to kill Alice, before the autopilot crashes the plane into the mountains and only Alice survives.
Six 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 a 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 Los Angeles, where they find survivors living in a prison which is surrounded by thousands of undead. They meet Luther West, (Boris Kodjoe) who leads the surviving band from the prison, Wendell (Fulvio Cecere), Crystal Waters (Kacey Clarke), Bennett (Kim Coates), Kim Yong (Norman Yeung), and Angel Ortiz (Sergio Peris-Mencheta). With their help, Alice finally 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 in exchange for freedom. Alice goes to the showers to wash up, but catches Wendell attempting to peep. Holding him at gunpoint, they are attacked by a group of infected people that dug into the prison. They take Wendell, but she manages to kill them.