The story revolves around Rex attempting to stop villain Van Kleiss from threatening the Earth. Rex journeys through the game collecting blueprints and evidence against Van Kleiss, while also trying to regain lost powers and absorb the nanites in infected people who have turned into monsters. As Rex is an amnesiac, clues to his past can be gathered throughout the game.
The gameplay features a mix of beat-em-up action and other genres, with players controlling Rex as he battles enemies and collects power-ups. The powers available to Rex include the Smackhands, Slam Cannon, BFS, Funchucks, and others, which must be re-earned as the player progresses through the game. Other stages feature driving and shooting sections, while the Providence headquarters allows for time trial challenges.