Born in Newark, New Jersey, Houston was the youngest of eight children of parents Nitch and Delia Drinkard. When Houston was 5 years old her mother, Delia, suffered a stroke and died of cerebral hemorrhage three years later. Her father, Nitch, later died of stomach cancer when Houston was 18.

As a child, Houston joined her sister Anne and brothers Larry and Nicky in the gospel singing group, the Drinkard Four. Houston's sister, Lee (who would later become the mother of singers Dee Dee and Dionne Warwick), later joined the group along with Ann Moss and Marie Epps, and the group was renamed the Drinkard Singers. Houston and the Drinkard Singers regularly performed at New Hope Baptist Church and later recorded a live album for RCA called A Joyful Noise.

Shortly after her father's death, Houston married her first husband at the age of 21. The two were divorced two years later while Houston was pregnant with her first son, Gary. Still pregnant, Houston met Army serviceman John Houston, and the two were married in 1959.

In 1963, then about to give birth to daughter Whitney Houston, she formed the Sweet Inspirations with Doris Troy and niece Dee Dee Warwick. Throughout the mid-1960s, the group provided backup vocals for several artists, including Aretha Franklin, Wilson Pickett, Lou Rawls, Otis Redding, The Drifters, and Van Morrison (for "Brown Eyed Girl"). Houston is the operatic soprano in the background on Franklin's hit, "Ain't No Way". The group also sang backup for Elvis Presley in a series of Las Vegas concerts during the late 1960s, and for Cissy's relative Dionne Warwick.

Houston left the Sweet Inspirations in 1969 to pursue a solo career. She was signed by Commonwealth United and recorded a well-received album in 1970 and several hit singles shortly thereafter, including covers of "I'll Be There" and "Be My Baby". After her contract was sold to Janus Records in the early 1970s, Houston recorded several more singles in the mid-1970s, and still more under the Private Stock label years later.