In 1931 at age 16, Harris dropped out of high school in North Omaha. The following year his first child, daughter Micky, was born to Naomi Henderson. Ten months later, Harris' second child, son Wesley, was born to Laura Devereaux. Both children were raised by their mothers. Wesley became a singer in the Five Echoes and the Sultans. Later he became the singer/guitarist in Preston Love's band.
In 1935 Harris, age 20, started dating 16-year-old Olive E. Goodlow (Ollie) of neighboring Council Bluffs, Iowa, who came to Omaha to watch him perform. On May 20, 1936, Ollie gave birth to daughter Pattie (Adrianne Patricia). On December 11, 1936, they married. Later they lived in the Logan Fontenelle projects in North Omaha. Ollie worked as a barmaid and nurse; Wynonie sang in clubs as well as taking on some odd jobs. Wynonie's mother Mallie Harris was Pattie's main caretaker. In 1940, Wynonie and Ollie Harris moved to Los Angeles, leaving Pattie with Mallie in Omaha.
He also began traveling frequently to Kansas City where he paid close attention to the great blues shouters of the time, including Jimmy Rushing and Big Joe Turner. Harris became a local celebrity in Omaha during the depths of the Depression (1935). In 1940 he and his wife moved to Los Angeles to seek more opportunity there. The city was a center of black migration. At that time Central Avenue in LA was becoming a center for musical performers. Harris' big break in Los Angeles was at a nightclub owned by Curtis Mosby called the Club Alabam. It was here that Harris became known as "Mr. Blues".
After the band's stint at the Apollo, they moved on to their regular residency at the Savoy Ballroom, also in Harlem. Here, Preston Love, Harris' childhood friend, joined Millinder's band replacing alto saxophonist Tab Smith.
On May 26, 1944, Harris made his recording debut with "Lucky Millinder and His Orchestra". Entering a recording studio for the first time, Harris sang on two of the five cuts that day, "Hurry, Hurry" and "Who Threw the Whiskey in the Well", for the Decca Records label. Although lessening, the shellac embargo had not yet been removed, and release of the record was delayed.
Harris' success and popularity grew as Millinder's band toured the country. He and Millinder had a falling out over money. In September 1945 while playing in San Antonio, Texas, Harris quit Millinder's band. Three weeks later, upon hearing of Harris' separation from the band, a Houston promoter refused to allow Millinder's band to perform. Millinder called Harris and agreed to pay Harris' asking price of one-hundred dollars a night. The promoter re-instated the date, but it was the last time Harris and Millinder worked together. Ben "Bull Moose" Jackson replaced Harris as vocalist of the band.
Harris returned to Los Angeles. He and Ollie moved their daughter Pattie, his mother and her husband from Omaha to Los Angeles. Harris resumed working at the Club Alabam.
In April 1945, a year after the song was recorded, Decca released "Who Threw the Whiskey in the Well". It became the group's biggest hit; it went to number one on the R&B charts on July 14 and stayed there for eight weeks. The song remained on the charts for almost five months, also becoming popular with white audiences, an unusual feat for black musicians of that era.
In California the success of the song opened doors for Harris. Since the contract with Decca was with Millinder (meaning Harris was a free agent), Harris could choose from the record deals with which he was presented.
In January 1946 Harris performed in Omaha for the first time since 1940. In late 1946 a performance was arranged at the Apollo (in Harlem), and he and Ollie moved to New York.
Harris went on to record sessions for other labels, including Apollo, Bullet and Aladdin. His greatest success came when he signed for Syd Nathan's King label, where he enjoyed a series of big hits on the US R&B chart in the late 1940s and early 50's. These included a 1948 cover of Roy Brown's original 1947 "Good Rocking Tonight, "Good Morning Judge", "Bloodshot Eyes", and "All She Wants To Do Is Rock".
In 1964 Harris resettled for the last time in Los Angeles. His final recordings were three sides which he did for the Chess label (in Chicago) in 1964: The Comeback, Buzzard Luck and Conjured. His final large-scale performance was at the Apollo (in New York) in November 1967, where he performed with Big Joe Turner, Big Mama Thornton, Jimmy Witherspoon and T-Bone Walker.