Originally from the Louisville suburb of Anchorage, Kentucky, Osborne moved to New York City in the late 1980s, where she formed her own record label, Womanly Hips, to release a few independent recordings before signing to Mercury Records; Soul Show was her first Album. Her second (and first major label) album is Relish (1995), which became a hit on the strength of the single "One of Us." The song was much more pop-oriented than the rest of the album, which was steeped in country, blues and folk music. "Right Hand Man" and "St. Teresa" were minor hits following the success of "One of Us." Her audience grew significantly with her appearance at Lilith Fair, which placed her in the same school of female singer-songwriters as Tori Amosand Sarah McLachlan. Her third studio album was Righteous Love, a long-delayed release, which fell off the charts quickly.

She was featured in the 2002 documentary film Standing in the Shadows of Motown and toured with legendary Motown sidemen the Funk Brothers. She and her band accompanied the Dixie Chicks for a national tour in the summer of 2003, during which time she also joined veteran San Francisco jam-rockers the Dead as a vocalist, and released her fourth album, titled How Sweet It Is, a collection of classic rock and soul covers.

During 2005 and 2006, Joan Osborne performed on numerous occasions with Phil Lesh and Friends. In February 2007, she appeared on the Grand Ole Opry.

In November 2006, she released Pretty Little Stranger, her self-described "Nashville album." It includes one song "After Jane" about a relationship with a woman. In May 2007, she issued Breakfast in Bed, a return to the soul music that she had covered on How Sweet It Is. Breakfast in Bed also featured the two songs ("Heatwave" and "What Becomes of the Brokenhearted") that she had covered for the film Standing in the Shadows of Motown.