The guitarist joins Johnny Cash tribute act Terry Lee Goffee in the game, which will be released for the PS2, PS3, Wii and 360.
Guitar Hero's Tim Riley said: "His accomplished career and breadth of musical style are a great illustration of the variety of rock experiences we have included in the game and we are excited to announce him as the first of five playable in-game artists."
Guitar Hero 5 will feature a live version of Santana's 'No One to Depend On' when it launches later this year.
