W.C. Handy began as bandmaster with Mahara's Minstrels starting in 1894 and remained with them until 1903. With Mahara's Minstrels he traveled to California, Canada, Mexico, and Cuba. In his autobiography, Handy offered an astute commentary of black minstrelsy:

It goes without saying that minstrels were a disreputable lot in the eyes of a large section of upper-crust Negroes...but it was also true that the best talent of that generation came down the same drain. The composers, the singers, the musicians, the speakers, the stage performers, the minstrel shows got them all. For my part, there wasn't a moment's hesitation when I received Elmore Dodd's letter. I took it for the break it was. The cards were running my way at last.⁷⁹

Indeed, his trip with the Mahara's Minstrels to Cuba would influence Handy's most important composition, St. Louis Blues, which incorporated the tango/habanera rhythms that struck him in Cuba.⁸⁰ After leaving Mahara's Minstrels Handy became the musical director for Edward "Boss" Crump, Memphis mayoral candidate. He composed the campaign song Mr. Crump. Whether Mr. Crump contributed to Crump's election as mayor is unclear, as many of the lyrics of Handy's song were likely unhelpful to the candidate: "Mr. Crump won't 'low no easy riders here/We don't care what Mr. Crump don't 'low/We gon'to bar'l-house anyhow-/Mr. Crump can go and catch hisself some air!"⁸¹ Handy transformed Mr. Crump into an instrumental Memphis Blues, and eventually sold the copyright to a man who he later referred to as "the exploiter" for fifty dollars. Memphis Blues was the first ever published blues composition.⁸² In 1914, Handy wrote St. Louis Blues, which became unquestionably one of the most important blues compositions in history. St. Louis Blues neared the top of the list of 40 Most Recorded Songs between 1900 and 1950.⁸³

In the three years following St. Louis Blues, Handy composed a rapid succession of blues classics including Yellow Dog Blues (recorded by Bessie Smith), Joe Turner Blues, and Beale Street Blues. In 1926 he edited the important, Blues: An Anthology. Handy's other important works include Aframerican Hymn, Aunt Hagar's Children Blues, Golden Brown Blues (words by Langston Hughes), and Blue Denim, a symphony in four movements. He is widely regarded as the "Father of the Blues" as the title of his autobiography suggests. Although few regard Handy as the originator of the Blues, his designation as its father comes from his reputation as the musician who first popularized the Blues, capturing its spirit.