Guitar Hero 5 is the fifth main game in the musical rhythm series. Similar to the previous title, Guitar Hero: World Tour, the focus is on a band-experience, with a lead and bass guitar, drums and vocals. The title is available standalone or bundled with the instruments.

Next to a new soundtrack with 85 songs, many animated lead singers are now modelled after famous musicians such as Johnny Cash, Carlos Santana, Shirley Manson, Kurt Cobain, and Matthew Bellamy. Players can still compose their own songs in the included studio and the game relies heavily on downloadable content, through tracks and full albums. A portion of the songs of Guitar Hero: World Tour, Guitar Hero Smash Hits and Band Hero can be imported in exchange for a small fee per song.

In the Band Lobby players can assemble a party of local and remote players to form a band, play the Career mode or opt for Quickplay. Most of the competitive multiplayer modes are carried over from former versions, along with two new ones: Party Play (random song selection with the option to join and leave at will using any instrument) and RockFest, a band mode for up to four (local) or up to eight (online) players with a variety of submodes. The songs are divided in smaller portions and for each section the players are rewarded based on a variety of conditions.

General new features introduced to the gameplay include drop-in/drop-out play, where it is possible to join in the middle of a song or stop playing without interrupting gameplay. There is also a new Challenges section in the Career mode.

The different game versions are identical, except for the PS2 version that lacks online game modes and downloadable content, drop-in/drop-out play and song challenges. It is also limited to two instruments and the multitap is not supported. The Wii version is very similar to the major console versions, including downloadable content on SD cards, multiplayer through the global Wii address book, and the Mii Freestyle mode from the previous game. It also supports interaction with the Nintendo DS to edit videos and provides access to the Roadie Battle mode, similar to the main battle mode of Guitar Hero III, where players complete mini-games on the Nintendo DS to sabotage the players on the console.