Rita Coolidge's early career was as a backing vocalist, for artists such as Joe Cocker, Eric Clapton, and Leon Russell. Her performance of "Superstar" on the Cocker/Russell Mad Dogs and Englishmen album helped gain her attention.

She became known as "The Delta Lady" and inspired Leon Russell to write a song of the same name for her. She is also the "sweet little Indian girl" mentioned in David Crosby's song "Cowboy Movie" released on his album If I Could Only Remember My Name. It was during this time that she met Kris Kristofferson; the two married in 1973. With him, she recorded several duet albums which sold well, and earned them a Grammy Award for Best Country Performance by a Duo or Group with Vocal in 1974 for From the Bottle to the Bottom, and in 1976 for Lover Please. She had several solo hit singles during the late 1970s with cover versions. Her first hit, "(Your Love Has Lifted Me) Higher and Higher," a cover of the Jackie Wilson song, was also her highest seller, reaching number two on the U.S. charts in 1977. She followed that with Boz Skaggs's "We're All Alone" which reached number seven later that same year.

Other hits were "One Fine Day" (written by Carole King and a hit for the 1960s girl group the Chiffons, "We're All Alone" (originally recorded by Boz Scaggs and also covered by Frankie Valli), "I Don't Want to Talk About It" (written by Danny Whitten), "The Way You Do the Things You Do" (The Temptations), and "I'd Rather Leave While I'm in Love" (Carole Bayer Sager). In 1980 Coolidge also was the voice of Melissa Raccoon in the Christmas Raccoons,and reprised this role for a subsequent special The Raccoons on Ice in 1981. Both of these specials served as a predecessor to the critically-acclaimed Canadian animated series the Raccoons.

She scored her last hit in 1983, with "All Time High" for the James Bond film Octopussy. Another well-known movie song, although not really a hit for Coolidge, was the love theme from the movie Splash, entitled "Love Came For Me".

In 1997, Coolidge was one of the founding members of Walela, a Native American music trio, that also includes Coolidge's sister Priscilla and Priscilla's daughter Laura Satterfield. The trio released albums in 1997 and 2000. Walela means hummingbird in Cherokee.

In 2004, Coolidge released an anthology of her complete career, entitled Delta Lady — The Rita Coolidge Anthology.