Mattea grew up in West Virginia and headed to Nashville to pursue her music career at 19. She boned up on country music history as a tour guide at the Country Music Hall of Fame.

Her first single was "Street Talk" from her 1984 self-titled debut album. It peaked at #25 on the Country chart, but Mattea was most excited by hearing herself on the radio for the first time. "I was actually sitting in my car on Music Row of all places," she recalled to Sturgis Journal. "I was at a red light, and Music Row is a one-way street, so there was a guy in a van next to me at the light. I started going nuts in my car and looked over at him, and pointed to myself and the radio trying to tell him I was hearing myself… He just looked at me and nodded, like 'Suuuuure you are.' And when the light turned green, he just took off."

Her first Top 10 on the Country chart was Nanci Griffith's "Love At The Five And Dime," which peaked at #3 in 1986. The following year, she landed her first #1 with another Griffith tune: "Goin' Gone."

She married songwriter/musician Jon Vezner in 1988. He co-wrote four of her singles: "Where've You Been," "Time Passes By," "Whole Lotta Holes," and "A Few Good Things Remain."

Mattea is a songwriter in her own right, but prefers to champion lesser-known songwriters by recording their tunes, such as Susanna Clark's "Come From The Heart," which she brought to the top of the country tally in 1989. "I've written some songs I'm proud of and I think I could have been a great writer if I stayed with it," Mattea, who wrote the semi-autobiographical song "Leaving West Virginia," explained in a Songfacts interview. "But I see myself as a singer who sometimes writes."

She's won two Grammy Awards: Best Female Country Performance for "Where've You Been" and Best Bluegrass, Country or Bluegrass Gospel album for 1993's Good News.

She's a noted campaigner for AIDS awareness and won the Harvard AIDS Initiative award in 1994.

She was one of the consultants on Ken Burns' 2019 Country Music documentary and appears in the film.

Mattea underwent vocal surgery in 1993, but her voice problems resurfaced years later, which forced her to re-learn how to sing. While practicing Bobbie Gentry's " Ode To Billie Joe" (included on her Pretty Bird album), she discovered a new facet to her voice that gave her hope moving forward. She told The Tennessean: "The low note in that song is a low C, and I've always been able to hit a low C, but I've never been able to use a low C. But something had opened up in the lower part of my voice. That was the day I thought, 'I could not sing this 10 years ago. And not only can I sing it, it brings forth what's beautiful about my voice today, what it could do that it never could before. It's not what I'm leaving behind, it's what I'm moving towards.'"