In this fourth Resident Evil movie, opening a few weeks the events of 'Resident Evil: Extinction', the Alice clones (Milla Jovovich) attempt to kill Umbrella CEO Albert Wesker (Shawn Roberts) at his base in Japan. All present clones are killed in as the facility is destroyed in an explosion, activated by Wesker as he escapes in an aircraft. The original Alice ambushes him, but Wesker injects her with a serum that neutralizes the T-virus in her system, eliminating her superhuman powers and making her human again. He reveals that his T-Virus powers have surpassed her own, but before he can kill her, the aircraft crashes and Alice emerges from the wreckage.
Six months later. Alice follows a repeating emergency broadcast from a survivors' safe haven known as "Arcadia" in Alaska. After many fruitless months searching for Arcadia and finding no survivors along the way, including her friends from the previous movie, Claire Redfield (Ali Larter) and K-Mart (Spencer Locke), Alice begins to lose hope, believing herself to be the last surviving human on the planet. Stopping on an abandoned beach, Alice finds the helicopter taken by Claire and the others when they and Alice parted ways. A crazed Claire, under the influence of an Umbrella Corporation device attached to her chest, attacks her. Alice removes the device, finding that it has damaged Claire's memory, which she slowly regains.
Flying a two-person plane, they enter the ruins of Los Angeles and find a small group of survivors, led by Luther West (Boris Kodjoe) living in a maximum security prison, surrounded by the undead. Alice crash lands the plane on the roof of the prison and learn that Arcadia is not a fixed place but actually a cargo tanker traveling along the coast. Since the plane cannot take more than two, Alice and the survivors try to figure out a means to make it to Arcadia together. The survivors have been keeping watch on a prisoner, Chris Redfield (Wentworth Miller), whom they found locked in a maximum security cell when they arrived. He says that he is a Umbrella soldier who fought the early outbreak, but was locked up by prisoners as a cruel joke when the mission failed and knows a way to reach the coast, and thereby Arcadia, but will not reveal it unless he is released.
They do not believe him, and keep him locked up until the undead manage to tunnel through the sewer ways and up into the prison, and a giant axe wielding monster (The Executioner) starts to break down the front gate; Alice and survivors are out of time to find a means to reach Arcadia so they decide to free Chris and use his escape route. He recognizes Claire and reveals himself as her brother, though she does not remember him. Chris' proposes using a military vehicle, stored somewhere in the prison. Discovering the vehicle is not operational Bennett uses the plane to escape. The remaining group has no option but to use the sewer tunnel. The group fights their way out Luther is trapped when the tunnel caves in - Alice, Claire, and Chris manage to escape through the sewers.
They continue to Arcadia, finding the ship completely functional, but abandoned. Exploring its inner depths, they realize that it is a trap set by Umbrella to lure survivors to the ship to conduct experiments on them. Claire now remembers what happened to her group when they arrived to Alaska: Umbrella troops ambushed their group when they landed on the beach, attaching the devices to them, though she managed to escape. They release the survivors, among them K-Mart, and Alice continues deeper into the ship, finding escape helicopters and a purge bomb. Deeper inward, she finds Wesker, who explains the price of his survival, is a war within himself for control against the T-Virus. He hopes to gain control of the virus by assimilating Alice, the only individual to bond successfully with the T-virus. At this point the crew of the ship had abandoned Wesker, terrified by his cannibalism.
Chris, Claire, and Alice battle the super-powered Wesker and seemingly kill him, with help from a recovered K-Mart. Wesker does not die, but rather regenerates and escapes again by helicopter, activating the purge bomb on the Arcadia in an attempt to destroy the ship and kill the remaining survivors. Anticipating Wesker's actions, Alice had hidden the bomb onboard his helicopter, which is destroyed as she watches from the deck of the Arcadia, with Claire and Chris. Momentarily blinded by the flash from the explosion, a figure parachutes away from the destruction unnoticed... implying that Wesker has survived yet again. Elsewhere, Luther emerges from the sewers, having escaped his infected attackers.
Alice resolves to turn Arcadia into a real safe haven and broadcasts its message for any other survivors. As Claire, Chris, and Alice decide how to proceed with all the survivors, they look up over the ocean to see an approaching Umbrella assault fleet of fix-winged helicopters loaded with murderous and heavily armed Umbrella troops. It is revealed that the troops are led by former Raccoon City police detective Jill Valentine (Sienna Guillory), who is under the control of the same Umbrella device used on Claire...