Henry Luther Threadgill is born February 15, 1944, and grows up on the South Side of Chicago. He starts on percussion, plays clarinet in the Englewood High School band, and switches to saxophone at fifteen. Before he is out of his teens he is working in local polka bands and Latin bands, in theater pit orchestras and marching bands, and playing blues at South Side rooms including the Blue Flame, all while studying at the American Conservatory of Music, where he majors in piano, flute and composition under Gail Quillman and Stella Roberts. At nineteen he joins Muhal Richard Abrams's Experimental Band, the workshop that becomes the Association for the Advancement of Creative Musicians in 1965, making him one of the AACM's original members. He leaves Chicago to tour with a gospel band, and in 1967 enlists in the U.S. Army as a clarinetist and saxophonist, doubling as composer and arranger, and is posted to Vietnam with the 4th Infantry Division Band. He is injured during the 1968 Tet Offensive and honorably discharged in 1969 with two campaign ribbons.

Back in Chicago he rejoins the AACM and, in 1972, forms a trio with bassist Fred Hopkins and drummer Steve McCall that becomes the group Air. Over eleven years Air makes a body of work that is unusually rigorous for a drums, bass and reeds trio, from Air Song (Whynot, recorded in Chicago in September 1975) through Air Time (Nessa, 1978) and Open Air Suit (Arista/Novus, 1978), a suite structured on card-game rules. Air Lore (Arista/Novus, 1979) turns the trio loose on Scott Joplin and Jelly Roll Morton, treating ragtime and early New Orleans repertoire as living improvisational material rather than antiquarian revival; the record is dedicated to the memory of the singer Eddie Jefferson. After McCall's departure, Pheeroan akLaff takes the drum chair and the band continues as New Air, closing with Air Show No. 1 (Black Saint, recorded in Milan in June 1986), on which a then little-known Cassandra Wilson sings.

Threadgill moves to New York and begins building ensembles around instrumentations no one else is using. X-75 is a nonet of four reed players, four bassists and a voice, documented on X-75 Volume 1 (Arista/Novus), cut in a single day in January 1979 with Joseph Jarman, Douglas Ewart and Wallace McMillan in the reeds, Fred Hopkins, Leonard Jones, Brian Smith and Rufus Reid on basses, and Amina Claudine Myers singing. The Henry Threadgill Sextett, a septet in which two drummers are counted as one percussion unit, records three albums for About Time and three for RCA's Novus imprint between 1982 and 1989, its front line rotating through Olu Dara, Craig Harris, Rasul Siddik, Frank Lacy, Ted Daniel and Ray Anderson over a rhythm section anchored by Hopkins, cellist Diedre Murray and the drum pair of akLaff with John Betsch, Reggie Nicholson or Newman Baker. You Know the Number and Easily Slip Into Another World are the group's most widely heard records. Through the same decade he holds the alto chair in David Murray's octet on Ming (1980), Home (1982) and Murray's Steps (1983), alongside Olu Dara, George Lewis, Butch Morris and Wilber Morris.

In 1990 he assembles Very Very Circus: two tubas, two electric guitars, trombone or French horn, drums and his own alto and flute. The band records for Black Saint and then, through producer Bill Laswell, for Axiom and Columbia, and Threadgill keeps enlarging it from the outside, adding Venezuelan percussion and voices, accordion, violin, the oud and violin of Simon Shaheen and the pipa of Wu Man on Too Much Sugar for a Dime (1993) and Carry the Day (1995). Song Out of My Trees (Black Saint, 1994) is scored for combinations that include three cellos and a bank of four guitars; Makin' a Move (Columbia, 1995) opens with a piece for four guitars and piano on which Threadgill does not play at all. Make a Move, the quartet that follows, pares the sound back to guitar, accordion and harmonium, five-string fretless bass and drums on Where's Your Cup? (Columbia, 1997) and Everybodys Mouth's a Book (Pi Recordings, 2001).

Zooid, formed in 2001, becomes the longest-running band of his career and the vehicle for the interval-based system he has been developing since the 1990s, in which each player improvises from an assigned series of intervals so that counterpoint, rather than chord changes, generates the harmony. Its instrumentation settles into acoustic guitar (Liberty Ellman), tuba and trombone (Jose Davila), cello (Christopher Hoffman, from 2011), acoustic bass guitar (Stomu Takeishi) and drums (Elliot Humberto Kavee). The band's In for a Penny, In for a Pound, premiered at Roulette Intermedium in Brooklyn on December 4, 2014, recorded four days later and issued by Pi Recordings in May 2015, wins the 2016 Pulitzer Prize for Music, the citation calling it "a highly original work in which notated music and improvisation mesh." He is one of a very small number of jazz musicians to have won the prize. Zooid continues with Poof (2021) and Cut You Where You Was, released in August 2026.

Since the mid-2010s Threadgill has worked increasingly as a composer directing ensembles he does not play in. Ensemble Double Up, built around paired pianos and paired alto saxophones, makes Old Locks and Irregular Verbs (2016), an elegy for Butch Morris on which Threadgill writes and conducts but plays nothing, with Jason Moran and David Virelles at the two pianos; 14 or 15 Kestra: Agg expands the same logic to fifteen players and two drummers on Dirt... And More Dirt (2018). The Other One (2023), recorded live at Roulette in May 2022, is a three-movement work for a twelve-piece ensemble of three saxophones, strings, two bassoons, tuba, piano and percussion, dedicated to the drummer and theorist Milford Graves. His string quartet "Sixfivetwo" was written for the Kronos Quartet's Fifty for the Future project in 2018. He is named an NEA Jazz Master in 2021 alongside Terri Lyne Carrington, Albert "Tootie" Heath and Phil Schaap, and his memoir Easily Slip Into Another World: A Life in Music, written with Brent Hayes Edwards, appears in 2023 and takes a PEN Oakland/Josephine Miles Award the following year. He remains based in New York and continues to record: Listen Ship (Pi, 2025), scored for four acoustic guitars, two acoustic bass guitars and two pianos with Threadgill conducting, and Fifteen (Nonesuch, 2026), a trio date with pianist Vijay Iyer and drummer Dafnis Prieto cut in November 2025.

Threadgill's music is genuinely compositional first and is often described as beyond category, and that is the accurate description rather than a critic's evasion: his catalogue is organized around instrumentations invented for particular pieces (four basses and a voice, two tubas and two guitars, three cellos, two pianos and two altos) and around a self-devised interval system that replaces functional harmony with a preconceived series each improviser works from, so that the ensemble's harmony emerges out of the counterpoint instead of being laid under it. The lineage is Chicago and the AACM: Muhal Richard Abrams's Experimental Band taught him that a working band could be a compositional laboratory, and the AACM's insistence on original repertoire is the premise every one of his groups rests on. Around that sits the South Side apprenticeship in polka bands, Latin bands, blues rooms, marching bands and church music, which is why marches, hymn cadences, ragtime and Caribbean rhythm keep surfacing in music otherwise built from materials closer to twentieth-century concert composition, most explicitly on Air Lore's Joplin and Morton readings. As a player he has a dry, biting alto sound and a flute tone with no sweetness in it, and he built his own instrument, the hubkaphone, a tuned rank of automobile hubcaps he plays on records from Air Time through Pop Start the Tape, Stop. The New York Times has called him "one of the most thrillingly elusive composers in and around the jazz idiom." His influence runs through younger players who came up on the records rather than the bandstand: drummer Chad Taylor heard Air as an undergraduate classical guitarist and changed instruments and cities because of it, later writing his Rutgers MFA thesis on form and process in Zooid, and pianist Vijay Iyer recorded Threadgill's "Little Pocket Size Demons" with his trio in 2011, fourteen years before the two of them made a record together.