The House of the Dead: Overkill is an episode of the zombie rail-shooter series specifically developed for the Wii controls. Players use the Wii Remote to aim, B button to shoot, and wiggle the remote to reload. The two main buttons are used to change weapons, and other actions such as throwing a grenade. The game is set before the events of the first episode and takes place in the town of Bayou City. Agent G teams up with Detective Washington to fight the plague of mutants, who they believed to be at the head of this mess: Papa Caesar.
The game has a different tone than previous episodes, adopting a vintage effect popularized in grindhouse movies. This is reflected in its over-the-top violence, taunts, and scenario, all designed to hint at playing a B-game.
There are three main modes available: Story Mode, Director's Cut Mode, and Mini-Games. Story Mode features the classic rail-shooter concept, divided into nine levels. Director's Cut offers enhanced and longer levels. Mini-games are mostly shoot challenges for multiple players, with rewards such as money that can be spent on upgrading weapons or buying new ones.
The game supports multiplayer for two players simultaneously. A unique feature allows a player to carry up to two different weapons.