The unofficial poet laureate of Harlem, Langston Hughes derived great inspiration from the everyday scenes and sounds of his surroundings. He was especially inspired by jazz and blues, spending hours in the nightclubs of Harlem and Washington, D.C., listening and writing. “I tried to write poems like the songs they sang on Seventh Street,” he said of his poetry. This influence is apparent in much of his work and can be seen clearly in such poems as "The Weary Blues," "Jazzonia," "Harlem Night Club," "The South," and Montage of a Dream Deferred, a book-length suite of poems illustrating Harlem life. In "The Weary Blues," he writes:

With his ebony hands on each ivory key
He made that poor piano moan with melody.
     O Blues!
Swaying to and fro on his rickety stool
He played that sad raggy tune like a musical fool.
     Sweet Blues!
Coming from a black man's soul.
     O Blues!

The poet's relationship to music stretches far beyond the rhythms and images of his poems: he also wrote musicals, operas, and cantatas, and he collaborated with several composers and jazz musicians. Many of his plays incorporated musical elements and song, such as the musical Simply Heavenly, and his three gospel plays: Black Nativity, Tambourines to Glory, and The Prodigal Son. Hughes authored music guides, including Famous Negro Music Makers, and the children's title, The First Book of Jazz. He also wrote liner notes for albums by Harry Belafonte and Nina Simone, who recorded a powerful setting of his poem "Backlash Blues."

Hughes worked with Kurt Weill on the musical Street Scene, which opened on Broadway in 1947, and tells the story of a woman in an abused marriage who is murdered for having an adulterous affair. With lyrics by Hughes and a score composed by Weill, the songs offer a stark portrayal of working class life, while combining the smooth hooks of pop music with an operatic sense of drama.

A long collaboration between Hughes and composer Jan Meyerowitz produced numerous works, including the operas The Barrier, Esther, and Port Town, as well as Five Foolish Virgins, an oratorio based on biblical text set to music, and the Easter cantata, The Glory Round His Head, which premiered in 1955 at Carnegie Hall. Working with composer William Grant Stills, Hughes wrote the libretto for Troubled Island, an opera by about the Haitian revolution. In 1965, he wrote the cantata Let Us Remember, with music by David Amram, commissioned for the biennial convention of Reformed Judaism.

In 1958, Hughes crossed into the jazz world by reading his work at the landmark Village Vanguard in New York City, accompanied by Charles Mingus and Phineas Newborn. The collaboration eventually resulted in the album The Weary Blues, which united Hughes’s voice and words with the music of Leonard Feather and Mingus. The first half of the album is conducted by Feather and features a traditional blues and gospel sound, while the latter half, with Mingus and his band, provides an organic jazzy groove for the poet's mellifluous voice to ride upon.