Yuro moved with her family to Los Angeles. There, she sang in her parents' Italian restaurant and in local clubs before catching the eye and ear of record executives. Signed to Liberty Records, she had a Top Ten hit in 1961 with "Hurt", an R&B ballad that had been an early success for Roy Hamilton. On "Hurt" and on her Top 20 follow-up, "What's a Matter Baby (Is It Hurting You?)", Yuro showed an emotional but elegant vocal style that owed a debt to Dinah Washington and other black jazz singers. Many listeners in the early 1960s thought Yuro was black. She opened for Frank Sinatra on his 1962 tour of Australia.

In 1963, Yuro released Make the World Go Away, an album of country and blues standards. The singer at her vocal peak, this recording includes a powerful title track of the same name, a beautifully understated version of Willie Nelson's "Permanently Lonely", and two different blues takes of "I'm Movin' On". Yuro was also known for soulful reworkings of popular American standards, such as "Let Me Call You Sweetheart", "Smile", and "I Apologize".

By the late 1960s, Yuro had performed in venues from London to Las Vegas. However, her career soon lost its early momentum, and she quit the music business altogether after her marriage in 1972. When Yuro began to sing again in the 1980s, her doctors detected throat cancer. Her larynx was eventually removed and in 2004 she succumbed to cancer. Her last recording was the 1984 CD Timi Yuro Sings Willie Nelson, produced by her old friend Nelson.