She began performing in local clubs in Texas. Singer Joe Barry saw her and introduced Lynn to producer Huey P. Meaux, who ran SugarHill Recording Studios and several record labels in New Orleans. Her first single, “You’ll Lose A Good Thing”, co-written by her and Meaux, was recorded at Cosimo Matassa’s J&M studio with session musicians including Mac Rebennack (Dr. John). Released by Jamie Records, it was a number 1 US Billboard R&B chart hit and Top 10 Billboard Hot 100 hit in 1962. The song was later recorded by Aretha Franklin and became a country hit record for Freddy Fender. Reggae artist Mikey Dread also based the melody of his 1989 single “Choose Me” on this song. Lynn also released an album, also titled You’ll Lose A Good Thing, which featured ten of her compositions.

Unusually for the time, Lynn was a female African American singer who both wrote most of her own songs and played a lead instrument. Soon Lynn was touring with such soul musicians as Gladys Knight, Stevie Wonder, Smokey Robinson, Dionne Warwick, Jackie Wilson, Sam Cooke, Otis Redding, James Brown, Al Green, Carla Thomas, Marvin Gaye, Ike and Tina Turner, the Temptations, and B.B. King. She appeared at the Apollo Theater, twice on American Bandstand. In 1965, she had her song, “Oh Baby (We’ve Got A Good Thing Goin’)” (1964) covered by the Rolling Stones on their album The Rolling Stones Now! in America and Out Of Our Heads in the UK. The song was also recorded by Bill Wyman’s Rhythm Kings, with Beverly Skeete lead singing. Lynn continued to record for the Jamie label until 1966 and had several more minor hits.

In 1966 she signed to Meaux’s Tribe label, and recorded “You Left the Water Running,” which was covered by Otis Redding among others. She signed for Atlantic the following year, and recorded another album, Here Is Barbara Lynn, in 1968. She married for the first time, at age 28, in 1970 and had three children. This, together with dissatisfaction with poor promotion by the record company, contributed to her decision to largely retire from the music business for most of the 1970s and 1980s. However, while living in Los Angeles, she occasionally appeared at local clubs, and released several singles on Jetstream and other small labels.

In 1984 she toured Japan, and recorded a live album, You Don’t Have to Go, which was released later in the US. She resumed her recording career after her husband’s death, and returned to Beaumont, Texas, where her mother lived. She also undertook further international tours, to Europe and elsewhere. In 1994, she recorded her first studio album for over twenty years, So Good, and released several more albums for various labels in later years.

She continues to reside in Beaumont, and was given a Pioneer Award by the Rhythm and Blues Foundation in 1999. In 2002, electronic musician Moby sampled Lynn’s “I’m A Good Woman” on his album 18.

She appears in the 2015 documentary film I Am the Blues.

In 2018, Lynn received the National Heritage Fellowship.