The story begins when the S.T.A.R.S. Alpha team is sent to the Arklay Mountains to investigate the disappearance of Bravo Team. After an attack by mutated creatures, Chris Redfield, Jill Valentine, Barry Burton, and Albert Wesker find refuge in an isolated mansion. There they discover that the mansion is filled with zombies, traps, and biological weapons, the result of experiments by the Umbrella Corporation. As players explore the mansion, they solve puzzles, collect items, and uncover Wesker's betrayal and the existence of the Tyrant, a powerful biological weapon.

The gameplay remains faithful to the GameCube remake, with fixed camera angles, tank controls, and an emphasis on resource management. The Wii version adds the ability to control using the Wii Remote and Nunchuk, providing an alternative way to aim and interact. The game also includes Crimson Head zombies, defensive weapons, and alternate scenarios depending on the player's choices.