Osborne was paying her own way through college and taking time off to earn money for another semester when, by chance, she sang at an open mic night at the Abilene Café.

She soon became immersed in NYC's live music scene, forming her own band and playing in nightclubs alongside groups like the Sweetones, Surreal McCoys, Spin Doctors, Blues Traveler, and the Holmes Brothers, and artists like Chris Whitley, Frankie Paris, and Jeff Buckley.

In 1991, she formed her own record label, Womanly Hips, to release her first full-length album, Soul Show: Live at Delta 88, and she began to tour around the Northeast, building a devoted regional following.

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.

The same year, Osborne appeared as a featured guest in the third season of the Transatlantic Sessions television series, performing "Saint Teresa", "Holy Water", and "Please Don't Tell Me How the Story Ends".

Osborne sang lead vocals on the cover of the Willie Dixon-penned "Spoonful" on Vivian Campbell's 2005 solo album, Two Sides of If.

She is featured on the Holmes Brothers 2007 collection State of Grace performing "Those Memories of You", an old Alan O'Bryant bluegrass tune.

In 2010, Osborne again produced an album for the Holmes Brothers on Alligator Records, Feed My Soul, which featured contributions from keyboard player Glenn Patscha.

In September 2012, Osborne was featured in a campaign called "30 Songs / 30 Days" to support Half the Sky: Turning Oppression into Opportunity for Women Worldwide, a multi-platform media project inspired by Nicholas Kristof and Sheryl WuDunn's book.

[4] Osborne was a member of Trigger Hippy, along with Steve Gorman, Tom Bukovac, Jackie Greene, and Nick Govrik.

[11] Raised a Roman Catholic, Osborne distanced herself from that institution after childhood, specifically after telling her parents that she wished to become a priest, only to learn that the Church does not allow women to do so.