She was discovered by Bill Anderson who took her to producer Bob Ferguson to sign a recording contract with RCA in 1963. The year after she hit first place in the country chart with "Once a Day" (written by Bill Anderson). This made her the first debuting female country star to reach no. 1 with the first single. "Once a Day" spent 8 weeks at number one, the biggest hit by a female vocalist ever on the Billboard country chart. Overnight she became a country music queen on a level with the biggest female names in the business: Kitty Wells, Loretta Lynn, Skeeter Davis, and Jean Shepard. Her other major 1960's hits include "Then and Only Then" (1965), "Ain't Had No Lovin'" (1966), and "Cincinnati, Ohio" (1967). Three of her albums hit number one on Billboard's country album chart. In all, she placed 31 albums on the Billboard country chart between 1965 and 1976. Smith had 20 songs place in Billboard's top ten between 1964 and 1976. Her last record to make the national charts was "A Far Cry From You" in 1985.

Smith remained at the top of the country field into the 1970's, switching to the Columbia label in 1973. She moved on to Monument Records in 1977 with less chart success and decided in 1980 to go into semi-retirement to spend more time with her children, singing only gospel songs in her appearances at the Grand Ole Opry. Renowned in the country music industry for her strong religious convictions, she has recorded gospel music throughout her career; nevertheless, her personal life has seen its ups and downs, including three unsuccessful marriages. Since 1997 she has been married to Marty Stuart, a country star 17 years her junior. Stuart produced Smith's 1998 comeback album on the Warner Brothers Records label. The duo frequently tour together and both remain popular acts on the Opry.