As with the previous Guitar Hero games, the player uses a guitar-shaped controller to simulate the playing of varying genres of rock music by playing notes as they scroll in-time with the music. Gameplay from the previous installments of the series has remained mainly intact, except for the addition of a new cooperative career mode.

Furthermore, the game includes Tom Morello (of Rage Against the Machine/Audioslave) and Slash (of Guns N' Roses/Slash's Snakepit/Velvet Revolver) as in-game characters. The Xbox 360, PlayStation 3 and PC versions also include Bret Michaels (Poison).