Based on the action-packed arcade game, Ghost Squad puts you in a a squad of three others as you traverse three different mission areas each comprised of multiple levels, unlocking 25 high-powered weapons as you progress. Within each level there are a series of selectable alternate routes that will provide the gamer with increasing challenges as enemies attack from unexpected places. Weapon selection is varied across a wide array of weapon types ranging from machine guns, submachine guns, pistols, sniper rifles, shotguns, and even crossbows.

The Wii version brings the arcade experience home and adds a number of new Wii-specific gameplay modes and features. The game features the use of the Wii Remote as a multi-purpose tool that allows players to easily control the targeting of on-screen enemies, defuse bombs, and rescue hostages.