Claire Redfield, senior member of an anti-bioterror organization Terra Save, attends a commemoration party in the TerraSave Headquarters. Claire meets her new partner, Moira Burton, older daughter of BSAA advisor Barry Burton. The party didn't end well as planned, as a group of masked assailants raid the headquarters and have Claire, Moira, and many other attendants captured.
When Claire comes to, she finds herself stranded in a dilapidated prison with Moira. They are not alone, however, as mysterious savage human monsters begin to stalk them through the labyrinthine prison. On their wrists a bracelet was installed, through which a female known as "Overseer" directs them around the compound, reciting poetry-like quotes. Making their way to the prison's communication tower, they discover that the prison is located on an island, much to their shock and disbelief they even doubt the distress message they sent through the tower's radio system would reach anybody.
Escaping the prison area, the Overseer commands them to reach a neighboring town called Wossek, where a group of abductees; Neil Fisher, Gabriel Chavez, and Pedro Fernandez, took refuge and plotted an escape plan. Claire also spots a mysterious young girl running away from them. Catching up to her, Moira calms the girl down, to which she introduces herself as Natalia Korda. The escape plan, now set in motion by Gabriel by using an abandoned helicopter, went completely wrong when the Overseer turns on the town's alarm system, herding monsters to their location, and sabotaging the helicopter's controls. Both Pedro and Gabriel lost their lives in the commotion.
Meanwhile, without Claire and Moira's consent, Natalia is abducted by an unknown figure. He took Natalia to a large building, where the Overseer is watching and contacting them, as per the survivors' deduction.
They proceed to Kierling, or as the Overseer calls it, "the place where everything comes to an end". To their dismay, the Overseer's henchmen had previously devised deadly traps around the area which Claire and Moira must disable or outsmart to move forward. Beyond the Kierling lies their final destination; the Overseer's tower. Claire and Moira discover the truth behind their abduction; Neil Fisher, mole of the previously disbanded FBC, is the true mastermind of the events so far. He sold TerraSave members to the Overseer now known as Alex Wesker, in exchange for a sample of Uroboros virus. Much to his shock, Alex injects him the very virus he requested earlier. Willing to dispose off the unneeded spy, Alex leaves Neil and as Claire catches up on him, he mutates into a huge Uroboros Tyrant-like monster, leaving his fate at Claire's hand. He was eventually killed by Moira, having overcoming her fear of guns.
They later use an elevator to reach her hideout, unaware that Alex had begun her own experiment using Natalia, placing the little girl inside a pod and sends her into the bowels of the facility. Alex greets Claire and Moira with a seemingly sardonic speech, briefly mentioning her brother, Albert and his experiments before drawing her gun to Claire, and inexplicably commits suicide. In response to the Alex's demise, her facility compound is set to self-destruct in several minutes.
Despite almost making their way out of the tower, Moira is trapped under falling debris, and forces Claire to jump out into the ocean below to avoid being blown to pieces.
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