The Johnson Brothers broke up in the mid 1930s, and Jackson began her solo career, recording for Decca in 1937. The result, "God's Gonna Separate the Wheat from the Tares" was only a moderate success, but Jackson became a popular concert draw. She experienced a recording hiatus until 1946 when she signed with Apollo Records, releasing several singles that are now highly regarded, though sales were sluggish at the time. "Move on up a Little Higher" (1948) became a huge success however, and stores couldn't stock enough of it to meet demand. Jackson rocketed to fame in the US, and soon after in Europe. "I Can Put My Trust in Jesus" won a prize from the French Academy, while "Silent Night" was one of the best-selling singles in the history of Norway. She began a radio series on CBS, and signed to Columbia Records in 1954. With her mainstream success came an inevitable backlash from gospel purists who felt she had watered down her sound for popular accessibility.

Jackson's career in the late 1950s and early 1960s continued to rise when she recorded with Percy Faith, and performed at the 1958 Newport Jazz Festival and the inauguration of John F. Kennedy. She also sang at the funeral of her friend, Martin Luther King, Jr. The late 1960s saw a downturn in her popular success. She ended her career with a concert in Germany in 1971; when she returned, she made one of her final television appearances on The Flip Wilson Show.

Jackson died in Chicago, Illinois on January 27, 1972 of heart failure and diabetes, at the age of 60. She was buried in Providence Memorial Park in Metairie, Louisiana. She was posthumously inducted into the Gospel Music Association's Gospel Music Hall of Fame in 1978.