Guitar Hero: Aerosmith is considered an expansion of Guitar Hero III and it is the first title in the series primarily focused on a single band. The gameplay concept is similar to the game it is based on. About 60% of the included tracks are by Aerosmith, while the others have influenced or have opened for the band (Run-D.M.C., The Kings, Lenny Kravitz, ...). Four songs were re-recorded by the band directly for the game and they also performed as motion capture actors for their 3D models. The majority of the tracks consists of master recordings.

The prominent game segment is the career mode where players go through the band's history, from the earlier seventies to 2001. Times of internal issues are not touched upon. Players initially start as Joe Perry but can later also unlock the other band members Brad Whitford and Tom Hamilton. The career has been divided into six tiers with five tracks, each based on a period in the band's history. There are also encores when a tier has been completed, and two opening acts playing as another band. After each tier, bonus material is shown such as trivia or video sequences and interviews.

Songs are unlocked gradually and become available in the other modes, identical to Guitar Hero III (Quickplay, Cooperative, Competitive + Battle modes). Only the cooperative career mode is absent. The menus have been redesigned and there are new venues, based on historical performances. There are 41 songs in total, of which 31 can be unlocked in the career mode and an additional 10 in the vault.

The game is available in a bundle with a custom guitar or as a single game release. For the PS2 version there are two bundles, one with a single, wireless guitar and another with two, wired guitars.