The game covers the entire Umbrella Chronicles storyline, all the way from the beginning Resident Evil 0, to the final destruction of the evil co-operation in the end of this new game. The Umbrella Co-operation is known for making various viruses during their attempt of creating genetically engineered soldiers. The story can be experienced from the perspective of the protagonists in the classic games, and also from new perspectives through the eyes of characters such as Albert Wesker and Rebecca Chambers of which the former was not playable before in the main storyline.

Resident Evil: The Umbrella Chronicles is an all-new instalment in the Resident Evil series that is released exclusively for Nintendo Wii. The game has players shoot their way through classic locations in Resident Evil 0, 1, 2, and 3, as well as never-seen-before locations, such as Umbrella's stronghold. The game is played from a first person perspective featuring light-gun style gameplay, using the Wii Remote Pointer Device to aim. The player is automatically navigated through the level 'on rails'. Throughout the game weapons can be customised to be made more powerful, and the archive can be filled by picking up special data items. The archive can later be referenced for interesting bits of information on specific items or characters featured in the Resident Evil series.