In September 1892, Handy travelled to Birmingham, Alabama, to take a teaching exam. He passed it easily and gained a teaching job at the Teachers Agriculture and Mechanical College (the current-day Alabama A&M University) in Normal, then an independent community near Huntsville. Learning that it paid poorly, he quit the position and found employment at a pipe works plant in nearby Bessemer.

Around that time, William Hooper Councill, the president of what had become the Alabama Agricultural and Mechanical College for Negroes (the same college Handy had refused to teach at in 1892 due to low pay), hired Handy to teach music. He became a faculty member in September 1900 and taught through much of 1902. He was disheartened to discover that the college emphasized teaching European music considered to be “classical”. He felt he was underpaid and could make more money touring with a minstrel group.

After the quartet disbanded, Handy went to Evansville, Indiana. He played the cornet in the Chicago World’s Fair in 1893. In Evansville, he joined a successful band that performed throughout neighboring cities and states. His musical endeavors were varied: he sang first tenor in a minstrel show, worked as a band director, choral director, cornetist, and trumpeter. At the age of 23, he became the bandmaster of Mahara’s Colored Minstrels.

In 1896, while performing at a barbecue in Henderson, Kentucky, Handy met Elizabeth Price. They married on July 19, 1896. She gave birth to Lucille, the first of their six children, on June 29, 1900, after they had settled in Florence.

In 1902 Handy traveled throughout Mississippi, listening to various styles of popular black music. The state was mostly rural and music was part of the culture, especially in cotton plantations in the Mississippi Delta. Musicians usually played guitar or banjo or, to a much lesser extent, piano. Handy’s remarkable memory enabled him to recall and transcribe the music he heard in his travels.

After a dispute with AAMC President Councill, Handy resigned his teaching position to return to the Mahara Minstrels and tour the Midwest and Pacific Northwest. In 1903 he became the director of a black band organized by the Knights of Pythias in Clarksdale, Mississippi. Handy and his family lived there for six years. In 1903, while waiting for a train in Tutwiler, in the Mississippi Delta, Handy had the following experience:

About 1905, while playing a dance in Cleveland, Mississippi, Handy was given a note asking for “our native music”. He played an old-time Southern melody but was asked if a local colored band could play a few numbers. Three young men with a battered guitar, mandolin, and a worn-out bass walked onto the stage. Research by Elliott Hurwitt for the Mississippi Blues Trail identified the leader of the band in Cleveland as Prince McCoy.

In 1909 Handy and his band moved to Memphis, Tennessee, where they played in clubs on Beale Street. “The Memphis Blues” was a campaign song written for Edward Crump, a Democrat Memphis mayoral candidate in the 1909 election and political boss. The other candidates also employed Black musicians for their campaigns. Handy later rewrote the tune and changed its name from “Mr. Crump” to “Memphis Blues.” The 1912 publication of the sheet music of “The Memphis Blues” introduced his style of 12-bar blues; it was credited as the inspiration for the foxtrot by Vernon and Irene Castle, a New York dance team. Handy sold the rights to the song for $100. By 1914, when he was 40, he had established his musical style, his popularity had greatly increased, and he was a prolific composer. Handy wrote about using folk songs:

His published musical works were groundbreaking because of his ethnicity. In 1912, he met Harry Pace at the Solvent Savings Bank in Memphis. Pace was the valedictorian of his graduating class at Atlanta University and a student of W. E. B. Du Bois. By the time of their meeting, Pace had already demonstrated a strong understanding of business. He earned his reputation by saving failing businesses. Handy liked him, and Pace later became the manager of Pace and Handy Sheet Music.

Writing about the first time “Saint Louis Blues” was played, in 1914, Handy said,

In 1917, he and his publishing business moved to New York City, where he had offices in the Gaiety Theatre office building in Times Square. By the end of that year, his most successful songs had been published: “Memphis Blues”, “Beale Street Blues”, and “Saint Louis Blues”. That year the Original Dixieland Jazz Band, a white New Orleans jazz ensemble, had recorded the first jazz record, introducing the style to a wide segment of the American public. Handy had little fondness for jazz, but bands dove into his repertoire with enthusiasm, making many of them jazz standards.

Expecting to make only “another hundred or so” of “Yellow Dog Blues” (originally entitled “Yellow Dog Rag”), Handy signed a deal with the Victor company. The Joe Smith recording of this song in 1919 became the best-selling recording of Handy’s music to date.

Handy tried to interest black women singers in his music but was unsuccessful. In 1920 Perry Bradford persuaded Mamie Smith to record two of his non-blues songs (“That Thing Called Love” and “You Can’t Keep a Good Man Down”) that were published by Handy and accompanied by a white band. When Bradford’s “Crazy Blues” became a hit as recorded by Smith, black blues singers became popular. Handy’s business began to decrease because of the competition.

In 1920 Pace amicably dissolved his partnership with Handy, with whom he also collaborated as lyricist. Pace formed Pace Phonograph Company and Black Swan Records and many of the employees went with him. Handy continued to operate the publishing company as a family-owned business. He published works of other black composers as well as his own, which included more than 150 sacred compositions and folk song arrangements and about 60 blues compositions. In the 1920s, he founded the Handy Record Company in New York City; while this label released no records, Handy organized recording sessions with it, and some of those recordings were eventually released on Paramount Records and Black Swan Records. So successful was “Saint Louis Blues” that in 1929 he and director Dudley Murphy collaborated on a RCA motion picture of the same name, which was to be shown before the main attraction. Handy suggested blues singer Bessie Smith for the starring role because the song had made her popular. The movie was filmed in June and was shown in movie houses throughout the United States from 1929 to 1932.

In 1926 Handy wrote Blues: An Anthology—Complete Words and Music of 53 Great Songs. It is an early attempt to record, analyze, and describe the blues as an integral part of the South and the history of the United States. To celebrate the publication of the book and to honor Handy, Small’s Paradise in Harlem hosted a party, “Handy Night”, on Tuesday October 5, which contained the best of jazz and blues selections provided by Adelaide Hall, Lottie Gee, Maude White, and Chic Collins.

In a 1938 radio episode of Ripley’s Believe it or not! Handy was described as “the father of jazz as well as the blues.” Fellow blues performer Jelly Roll Morton wrote an open letter to Downbeat magazine fuming that he had actually invented jazz.

Handy was born in Florence, Alabama, the son of Elizabeth Brewer and Charles Barnard Handy. His father was the pastor of a small church in Guntersville, a small town in northeast central Alabama. Handy wrote in his 1941 autobiography, Father of the Blues, that he was born in a log cabin built by his grandfather William Wise Handy, who became an African Methodist Episcopal minister after the Emancipation Proclamation. The log cabin of Handy’s birth has been preserved near downtown Florence.

After the publication of his autobiography, Handy published a book on African-American musicians, Unsung Americans Sung (1944). He wrote three other books: Blues: An Anthology: Complete Words and Music of 53 Great Songs, Book of Negro Spirituals, and Negro Authors and Composers of the United States. He lived on Strivers’ Row in Harlem. He became blind after an accidental fall from a subway platform in 1943. After the death of his first wife, he remarried in 1954 when he was 80. His bride was his secretary, Irma Louise Logan, who he frequently said had become his eyes. In 1955, he suffered a stroke, after which he began to use a wheelchair. More than eight hundred attended his 84th birthday party at the Waldorf-Astoria Hotel.

On March 28, 1958, Handy died of bronchial pneumonia at Sydenham Hospital in New York City Over 25,000 people attended his funeral in Harlem’s Abyssinian Baptist Church. Over 150,000 people gathered in the streets near the church to pay their respects. He was buried in Woodlawn Cemetery in the Bronx.