Antone's has been a haven for blues music in Austin. It was opened originally on Sixth Street by Clifford Antone on July 15, 1975. Antone feared that blues was in danger of disappearing. From its inception his club has attracted a variety of influential musicians. "Me and my friends," Antone said, "wanted to hear blues before these [musicians] died." The first act to perform at the club was zydeco legend Clifton Chenier and His Red-Hot Louisiana Band. In the weeks that followed, both Sunnyland Slim and Big Walter Horton, blues legends in their own right, attracted large crowds to the club. The club has relocated several times—first to Anderson Lane around 1980, then to Guadalupe Street in 1981, and to West Fifth Street in 1997. Antone’s moved to East Riverside in 2013.
Through the years the venue has promoted many new as well as established blues musicians and has garnered national and international attention in the process. The club helped the city of Austin claim its billing as the "Live Music Capital of the World." Antone's has hosted an impressive number of blues masters, including Muddy Waters, B. B. King, John Lee Hooker, Jimmy Reed, Otis Rush, Albert King, Lou Ann Barton, Angela Strehli, and the Fabulous Thunderbirds. Stevie Ray Vaughan and Doug Sahm regularly performed at Antone's. The sounds of blues, however, are not the only ones heard at Antone's. Musicians of all types are frequently on the playbill. In recent years Bonnie Raitt, Lucinda Williams, and Bono joined local bands to perform there.
By 1987 Antone had established Antone's Records which recorded both live shows and studio sets. The nightclub and the record label have produced recordings of guitarist Eddie Taylor, James Cotton (whose record was nominated for a Grammy Award), Mel Brown, and Memphis Slim. The label's release of Doug Sahm's Juke Box Music earned an Indie, the award of the National Association of Independent Record Distributors and Manufacturers, in 1989. Antone was awarded a Lifetime Achievement Award by the National Blues Foundation for his contributions to music. The venue has won many Austin Music Awards and was honored as Nightclub of the Year by USA Today. Clifford Antone died on May 23, 2006. That same year SilverStar Entertainment released the documentary film Antone's: Home of the Blues, which received a Keeping the Blues Alive Award from the Blues Foundation in 2007. Since the mid-1980s ownership of the club has consisted of a board of directors headed by Susan Antone, Clifford Antone's sister.
In 2013 a group of investors that included Austinite Arnold Wells, his brother Spencer Wells, musician Peter Grieser, and others purchased Antone’s. They closed the Riverside location in late 2013 in order to seek out a new location downtown. In March 2015 the new owners announced that they would be moving into the two-story Maxey Glass Company building located on East Fifth Street and just within a few blocks of the club’s original site. The new location offered 5,800 square feet on each floor, and plans were made for the club (with a capacity of 350 to 400), a gift shop, a green room for artists, office space, and retail space.
On June 3, 2015, KGSR’s Blues on the Green concert series held a fortieth anniversary celebration of Antone’s at Zilker Park. The event was hosted by Jimmie Vaughan.