Manhunt 2 takes place at the Dixmor Insane Asylum, where staff use violent methods to control patients instead of providing treatment. A power outage leads to a patient uprising, allowing the player to take on two roles: Dr. Daniel Lamb and Leo Kasper.
The gameplay is stealth-oriented, but later levels introduce third-person shooter elements with available firearms. Cover mechanics, movements, and stealth are crucial for success. A radar system indicates enemy awareness levels, and players can use objects or noise to distract them. To hide in the dark, a quick mini-game must be completed within time limits.
Players can perform executions, featuring three styles: Hasty, Violent, and Gruesome, with explicit violence including strangling, beatings, and gun violence. The Wii version requires players to mimic kill motions using the Wiimote and Nunchuk. All versions share similarities, but the Wii edition includes exclusive weapons, a short tutorial, and additional features.