Davis was the first of seven children born to william Lee and Sarah Rachel Roberts Penick, in Dry Ridge, Kentucky. Because her grandfather thought she had a lot of Energy for a young child, he nicknamed Mary Frances "Skeeter" (slang for mosquito). The Penick family moved to Erlanger, Kentucky, in 1947, where Skeeter met Betty Jack Davis at Dixie Heights High School, becoming instant friends. They sang together through much of high school, and at Decoursey Baptist Church. They formed the duet known as the Davis Sisters (although they were unrelated), and started singing on Detroit radio station WJR's program Barnyard Frolics. Eventually, the duo was signed by RCA Victor in 1951. Earlier demonstration recordings were eventually released on Fortune Records.

While "I Forgot More Than You'll Ever Know" was climbing the charts, the Davis Sisters were involved in a major car accident on August 1, 1953. The crash killed Betty Jack Davis and left Skeeter with severe injuries. After the accident, Skeeter and Betty Jack's sister, Georgia, continued as the Davis Sisters. Skeeter decided to retire from the music industry in 1956, and get married, ending the duet.

Davis decided to go back into country music as a solo act in 1958. She began touring with Ernest Tubb, and she returned to RCA Victor, this time working with Guitarist and record Producer Chet Atkins. That year, Davis recorded "Lost to a Geisha Girl", an answer song to Hank Locklin's hit "Geisha Girl", which reached the country number 15 and became her first solo hit. Atkins worked with Davis as a Guitarist on all of these sessions. At Davis' suggestion, Atkins frequently multiple-tracked Davis' voice for harmony vocals to resemble the sound of the Davis Sisters. This echo can be found on several of her early solo hits, such as "Am I That Easy to Forget".

Davis had a top-five country hit, "Set Him Free", in 1959, and another top-20 hit called "Homebreaker". She also joined the Grand Ole Opry that year, and was nominated for a Grammy Award for "Set Him Free", becoming the first female country singer to be nominated for a Grammy.

Davis lived in Brentwood, Tennessee, from the early 1960s until her death in 2004. Her autobiography, Bus Fare to Kentucky (named after a 1971 song), was published in 1993. In 1998, she wrote a children's book, The Christmas Note, with Cathie Pelletier.

Another big 1963 hit was "I'm Saving My Love", written by Alex Zanetis.

Davis' success continued with "I'm Saving My Love" and 1964's Gonna Get Along Without You Now, an updated cover a 1956 hit by Patience and Prudence). Both made the top 10 on the country charts and cracked the Billboard Top 50 pop charts, though the success of "Gonna Get" was likely hampered by another remake of the song by vocalist Tracey Dey simultaneously climbing the charts to peak slightly lower than Davis' version. Later pop efforts, such as "Let Me Get Close to You" in July 1964, missed making the Billboard Hot 100, reflecting the changing nature of pop styles due to the ongoing British invasion, but Davis continued a successful run on the country charts.

In 1965, she recorded a duet with Bobby Bare called "A Dear John Letter", which just missed the country top 10 and received light pop action. (The best-known version of the song had been recorded originally by Jean Shepard and Ferlin Husky in 1953.) Davis also recorded quite a few albums during this time, including two tribute albums I Love Flatt and Scruggs and Skeeter Davis Sings Buddy Holly. In 1967, Davis was back in the top 10 with "What Does It Take (To Keep a Man Like You Satisfied)". Davis only achieved two other major country hits the rest of the decade, "Fuel to the Flame" (written by Dolly Parton, to whom Davis paid tribute with an album called Skeeter Sings Dolly in 1972), and "There's a Fool Born Every Minute". Other singles were minor hits, but she released many albums.

In 1970, Davis had another top-10 hit with "I'm a Lover (Not a Fighter)" and another duet with Bobby Bare with "Your Husband, My Wife". The following year, she had a hit with the autobiographical "Bus Fare To Kentucky". Subsequently, however, her chart success began to fade. Singles such as "It's Hard to Be a Woman" and "Love Takes a Lot of My Time" failed to crack the country top 40. "One Tin Soldier" did not get much attention from country radio, but was nominated for a Grammy as Best Female Country Vocal. The record was a major success in Canada, however, peaking at number two on the easy listening chart and number four country. Her last major hit was 1973's "I Can't Believe That It's All Over", which peaked at number 12 in country and number 101 on the pop chart. In the 1970s, she began regularly touring foreign countries such as Barbados, Singapore, and Sweden, where she was among the most popular entertainers of any field.

Davis had the first and only controversy of her career when during a 1973 Grand Ole Opry performance, she dedicated a gospel song to a group of young church workers whom she noted in her introduction had been arrested for evangelizing at a local mall. The Opry suspended her from membership after receiving complaints from some local policemen. She was reinstated at the Opry more than a year later. After losing several bookings during that period, Davis became active singing with a number of religious ministries and spent an extensive period evangelizing in Africa.

Davis returned to the recording studio in 1976 with a brief stint on Mercury Records, which produced two single releases, including her last song to make the national charts, 1976's "I Love Us". In 1978, she recorded the first of several albums for minor record labels which she did on occasion into the 1990s.

In 2001, she became incapacitated by breast cancer. Davis remained a member of the Grand Ole Opry until her death, making her last appearance there in 2002. She died of breast cancer in a Nashville, Tennessee, hospice at the age of 72, on September 19, 2004.