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.