Harris graduated high school as class valedictorian and won a dramatic scholarship to the University of North Carolina at Chapel Hill. It was around that time that Harris began to seriously study music, heavily influenced by artists like Bob Dylan and Joan Baez.
Harris married fellow songwriter Tom Slocum in 1969, and recorded her first album the following year, entitled Gliding Bird. After the album's release, Harris' record label declared bankruptcy. Around that same time, Harris' marriage to Slocum began to fall apart and the couple were soon divorced. Harris, who lived for a brief time on her own with her newborn daughter Hallie in Nashville, Tennessee, was forced, after struggling financially, to move back in with her parents, who were now living in Washington, D.C..
Harris soon returned to performing, as part of a trio with local musicians Gerry Mule and Tom Guidera. One night, in 1971, members of the country group the Flying Burrito Brothers happened to be in the audience, including former Byrds member Chris Hillman, who took over the band after the departure of its founder Gram Parsons. Hillman was so impressed by Harris that he briefly considered asking her to join the band. Instead, in 1972, Hillman ended up recommending her to Parsons, who was looking for a female vocalist to work with on his first solo album. Harris toured as a member of Parsons' "Fallen Angels" band, and in 1973, Harris returned to the studio with Parsons to record Grievous Angel. Parsons was found dead in his hotel room on September 19, 1973, from an overdose of drugs and alcohol.
Returning to D.C., Harris reunited with Guidera to form "The Angel Band". That band released its debut album in 1975 on Reprise Records, entitled Pieces of the Sky. The album included a number of cover songs, including The Beatles' "For No One", and Harris's first hit single, The Louvin Brothers' "If I Could Only Win Your Love". A Christmas single was released shortly after entitled "Light of the Stable," which featured backing vocals from singers Dolly Parton, Linda Ronstadt, and Neil Young. In the mid 1970s, Harris began to work on albums for other major artists including Young, Rondstadt and Bob Dylan.
About ten years later, Harris would team up once again with Parton and Ronstadt for the album Trio. In 1980, she recorded "That Lovin' You Feelin' Again" with rock legend Roy Orbison for which they would win the Grammy Award for best vocal duo.
In 1995, Harris released Wrecking Ball, produced by Daniel Lanois, best known for his work with U2, Peter Gabriel, and Bob Dylan. An experimental album for Harris to say the least, the record included Harris' rendition of the Neil Young penned title track, Julie Miller's "All My Tears", Jimi Hendrix's "May This Be Love" and Gillian Welch's "Orphan Girl." U2's Larry Mullen, Jr showed up to play drums for the project.
In 1998 Harris released Spyboy, backed with a new band which included Nashville producer and songwriter Buddy Miller.
In 2000 Harris guested on Alternative country singer Ryan Adams' solo debut Heartbreaker. The same year she joined an all star group of traditional country, folk and blues artists for the T-Bone Burnett produced soundtrack to the Coen Brothers film, O Brother, Where Art Thou?. A documentary/concert film was also released about the making of the soundtrack, which is entitled Down From The Mountain. In 2002, Harris joined many of the same artists on the road for the Down From The Mountain Tour.
Since 1999, Harris has been organizing an annual benefit tour called "Concerts for a Landmine Free World." All proceeds from the tours support the Vietnam Veterans of America Foundation's (VVAF) efforts to assist innocent victims of conflicts around the world. The tour also benefits the VVAF's work to raise America's awareness of the global landmine crisis. Artists that have joined Harris on the road for these dates include Mary Chapin Carpenter, Bruce Cockburn, Steve Earle, Joan Baez, Patty Griffin and Nanci Griffith.