Overkill is a rail shooter, with pre-determined character movement, while the shooting element under player control by pointing the Wii Remote at the screen, moving the aiming reticle. The player can point the reticle near the edge of the screen to move the camera angle slightly in that direction, allowing a further field of view known as "Danger Cam". The story mode can be played solo or with another human player, with one weapon or dual-wielding controls.

Years ago during the Cold War, the U.S. military made a new superhuman formula called Formula X but the project for its use failed. The bunker for the experiments was shut down and abandoned. In 1991, seven years before The Curien Mansion Incident, AMS Special Agent G is given his first assignment and sent to a small town in Louisiana to investigate a series of disappearances and hunt down a deranged crime boss, Papa Caesar. Due to the presence of mutants, G is forced to team up with police detective Isaac Washington who is out to avenge his father's murder, which Caesar masterminded.