Local music enthusiasts opened the venue in January 14, 1977. The name was inspired by a well-known song by Professor Longhair who also performed there until his death in 1980. Before adopting use of "Tipitina's" as its name, the facility was known as "The 501 Club," in reference to its street address (501 Napoleon Avenue). Tipitina's stands as one of the best-known clubs in New Orleans. The building itself was constructed in 1912, and prior to becoming Tipitina's, it served as a gambling house, gymnasium, and brothel.
In the early years, it had a juice bar and restaurant as well as a bar. The only remnant of the juice bar is the banana in Tipitina's logo. In the early 1980s, the studios of radio station WWOZ were located in one of the apartments upstairs from the club. Tipitina's closed for a time during the 1984 World's Fair, when much of the local music scene was drawn to venues in and around the Fair. The building was then remodeled to remove the upstairs apartments in favor of a higher ceiling in the downstairs music venue and reopened.
In 1998, Tipitinas opened a second location on North Peters Street in the French Quarter, which for a time was also a regular live music venue but is currently used for private events and parties. Apart from running these venues, Tipitina's has established Tipitina's Foundation, a non-profit organization to support local music and musicians. The foundation has been especially active in supporting the musicians victimized by Hurricane Katrina.
During the annual New Orleans Jazz & Heritage Festival period, Tipitina's hosts a concert series entitled "Fess Jazztival", which is a play on "Jazz Festival" and Professor Longhair's nickname, "Fess".