Her desire and ability to sing came early and at age seven she was offered her first recording contract which her father turned down. However, she did make a spectacular professional debut. Wrapped in the American flag, and accompanied by 300 accordions, nine-year-old Warnes sang "The Star Spangled Banner" at Los Angeles' Shrine Auditorium.

After graduating from high school she was offered an opera scholarship but chose to sing folk songs, popular at the time. In 1968 she signed with Parrot Records (a Decca subsidiary) and recorded her first LP. That same year, she joined the cast of the television show, The Smothers Brothers Comedy Hour.

In 1970 she met Canadian poet/songwriter Leonard Cohen who profoundly influenced her career. She would eventually tour Europe with Cohen's band as a back-up singer and would record guest vocals for Cohen's albums Live Songs, Various Positions, I'm Your Man, and The Future. Cohen's Recent Songs included a duet on "The Smokey Life". In January 1987, Warnes released her album Famous Blue Raincoat: Songs of Leonard Cohen.

Her 1977 single "Right Time of the Night" brought her wide acclaim with the song going to #1 on Billboard's Adult Contemporary Singles chart. In 1980 she sang the Academy Award winner for Best Original Song, "It Goes Like It Goes" from the motion picture Norma Rae.

Warnes' 1981 song "One More Hour", composed by Randy Newman and recorded as part of the soundtrack album from the motion picture Ragtime, was nominated for an Academy Award. The following year she teamed up with Joe Cocker to sing Buffy Sainte-Marie's song "Up Where We Belong". Written for the motion picture, An Officer and a Gentleman, the song would be released as a single and hit #1 on Billboard's Hot 100 chart. In 1983 she and Cocker won the Grammy Award for Best Pop Performance by a Duo or Group with Vocal for "Up Where We Belong", while earning the songwriters (Buffy St. Marie and Jack Nitzsche) the Golden Globe Award and the Academy Award for Best Original Song.

In 1987, at the Coconut Grove in Los Angeles, she sang female background vocals with k.d. lang and Bonnie Raitt for Roy Orbison's television special A Black and White Night. That same year her duet with Bill Medley, "(I've Had) The Time of My Life", was included on the Dirty Dancing motion picture soundtrack album and reached #1 on the Billboard Hot 100 as a single. The song won the 1988 Grammy Award for Best Pop Performance by a Duo or Group with Vocal and the Academy Award for Best Original Song.

She also performed a duet with B. J. Thomas on the theme song for Growing Pains.