Tillis has scored nearly six dozen country and crossover hits from the years 1958 to 1988. His biggest country hit, 1972's, "I Ain't Never" had been a major hit for Webb Pierce in 1959. He was honored as the Country Music Association "Entertainer of the Year" in 1976. As a songwriter, Tillis' song "Detroit city" was a number one hit on the U.S. country charts in 1963 for Bobby Bare, and has since been covered by a number of other artists, including Dolly Parton.

In addition to his musical talents, Mel Tillis has acted in a number of motion pictures, including The Cannonball Run and Smokey and the Bandit II, as well as making guest appearances on a number of television series.

Tillis is known for a trademark stutter which disappears when he sings. A story about Tillis was that he would order "grits" in a restaurant he would frequent at as a struggling singer, because this was the only dish that he could pronounce clearly. His autobiography is titled "Stuttering boy".

In 1972, he was inducted into the Nashville Songwriters Hall of Fame.

His daughter is the successful country music artist Pam Tillis. As of 2005, Mr. Tillis is living in Ocala, Florida.