A large portion making up the center of the touch-screen doubles as a map. Accessing items in inventory, interacting with elements in the game environment, or jumping or crouching are all done with various buttons and options on the touch-screen.

The only button used regularly is L (or R for southpaws) to attack or fire weapons. Players move with the D-pad or, for southpaws, the ABXY buttons, and look around or target using the touch-screen. Gameplay Dementium II plays similar to the first game, and other Nintendo DS First-Person Shooters. This somewhat questionable therapy once again sees William fighting through a horrific nightmare world that switches from his prison-turned-hospital to a monster and demon-infested alternate vision. Whereas the first game had William fighting his way out of his dark dreamworld as part of a therapy method known as 'Phase 1.' Dementium II opens with 'Phase 1' considered a success, and now has William tasked with working through 'Phase 2' of his treatment. Story Dementium II follows the story of the first game where players take control of brain-surgery recipient William Redmoor as he is tasked with fighting and attempting to overcome the nightmarish monsters he sees. Dementium II is the follow-up to the DS exclusive First-Person Shooter horror title Dementium: the Ward.

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