Gainesville is traditionally well-known for its music scene and has spawned a number of bands and musicians including Tom Petty and the Heartbreakers, Steven Stills, Don Felder and Bernie Leadon of The Eagles, Against Me!, Less Than Jake, Hot Water Music, Sister Hazel, Roach Motel, I Hate Myself, and For Squirrels. It is also currently the location of independent labels No Idea Records and Plan It X Records. No Idea puts on the annual 3 day rock festival known as The Fest.

Between 1987 and 1992 Gainesville was a big rock scene, with Hollywood star River Phoenix having the local Hardback Cafe as his main base. Together with N-Dolphin, Tone Unknown and many others, River's band Aleka's Attic was a constant feature of the rock scene. The Phoenix family is still a presence in Gainesville with Rain Phoenix's band Papercranes and Liberty Phoenix's eco friendly store, Indigo.

During the mid to late 90's, punk and ska defined the local scene and saw the rise of several of the bands listed above.

Today, Gainesville is still known for its strong music community and was named "Best Place to Start a Band in the United States" by Blender Magazine in March of 2008. The article cited the large student population, cheap rent, and friendly venues as reasons why. Furthermore, the University of Florida supports local music by hosting local, regional, and national bands on a regular basis via various student organizations. Starting in 2008, Gainesville will host The Real Big Deal, a two day festival featuring national acts and camping.

Currently, punk has moved aside (while still present) and made room for all genres of music to succeed. Over the past decade, Gainesville has been home to everything from the latin,afrobeat sounds of Umoja Orchestra, the hardcore sound of Cutman, the indie rock Beat Buttons, the psychedelic rock of Morningbell, the epic rock of Liquid Limbs, the electronica, industrial collective Electronic SubSouth, the North Central Florida Blues Society, the alt country Swayze, the reggae sounds of The Duppies, ska staples The Know How, and countless others.

As of summer 2008, the town supports over a dozen music venues, such as The Common Grounds, The Atlantic, Market Street Pub, and 1982.

The music community is well served by the website www.gainesvillebands.com, which is a free open forum for all things music in Gainesville.

Gainesville's reputation as an independent music mecca can be traced back to October 1984 when a local music video station was brought on the air. The station was called TV-69, broadcast on UHF 69 and was owned by Cozzin Communications. The channel drew a lot of local media attention thanks in part to its promotion by famous comedian Bill Cosby, who was part-owner of that station when it started. TV-69 featured many videos by punk and indy-label bands and even had several locally produced videos ("Clone Love" by a local parody band, and a Dinosaur Jr song).