Ishmael Wadada Leo Smith was born December 18, 1941, in Leland, Mississippi. He began playing drums, mellophone, and French horn in his high school's concert and marching bands before settling on trumpet, absorbing the Mississippi Delta blues and improvisational traditions around him from an early age. His early musical training came from his stepfather, guitarist Alex Wallace, followed by the U.S. Military Band program in 1963 and Chicago's Sherwood School of Music from 1967 to 1969. After playing in R&B combos and Army bands through the early 1960s, he became a member of Chicago's Association for the Advancement of Creative Musicians (AACM) by 1967 and co-founded the trio Creative Construction Company with violinist Leroy Jenkins and saxophonist Anthony Braxton, which toured Europe in the late 1960s. In 1971 he founded his own label, Kabell Records, to release his music, starting with the solo album Creative Music - 1 the following year. He also formed the New Dalta Ahkri, a band whose shifting membership included Henry Threadgill, Anthony Davis, and Oliver Lake. By the early 1970s he had begun developing the graphic notation system he calls Ankhrasmation, formally dated by Wikipedia's sourced account to 1970.

From 1975 to 1976, Smith studied ethnomusicology at Wesleyan University while teaching at the University of New Haven, and it was during this period that Creative Construction Company reunited to record a self-titled album with Ornette Coleman supervising the session. After leaving Wesleyan he again played with Braxton and recorded with guitarist Derek Bailey's improvising collective Company. He released Spirit Catcher on Nessa Records in 1979 and signed a non-exclusive deal with Manfred Eicher's ECM label the same year, which issued the widely praised Divine Love. Through the 1980s he worked extensively in Europe with bassist Peter Kowald and percussionist Günter Sommer, recording Touch the Earth (1980) and If You Want the Kernels, You Have to Break the Shells (1983) for the German FMP label, and taking up the mbira (African thumb piano) as a recurring voice in his music. In the mid-1980s he became a Rastafarian and adopted the name Wadada, releasing Human Rights (1986) on Kabell/Gramm with Kowald and Sommer. He taught at Bard College from 1987 to 1993, when he moved to the California Institute of the Arts' Herb Alpert School of Music, remaining on the CalArts faculty until 2014 and directing its MFA program in African American Improvisation; his second ECM album, the solo Kulture Jazz, appeared in 1993.

Smith began his long association with John Zorn's Tzadik label in 1996 with Tao-Njia, and in 1998 he and guitarist Henry Kaiser launched Yo Miles!, an electric ensemble devoted to Miles Davis's then-underappreciated 1970s electric period, releasing a self-titled debut that year followed by Sky Garden and Upriver (both Cuneiform, 2004-2005). In 2000 he formed the Golden Quartet for its Tzadik debut with Jack DeJohnette on drums, Anthony Davis on piano, and Malachi Favors on bass; the group's personnel rotated over the years to include bassist John Lindberg, drummer Pheeroan akLaff, pianist Vijay Iyer, and drummer Ronald Shannon Jackson, expanding at times into a Golden Quintet. He reunited with Braxton for Organic Resonance (2003) and Saturn, Conjunct the Grand Canyon in a Sweet Embrace (2004) on Pi Recordings, both issued as the two men's leader catalogs kept expanding on separate but overlapping paths.

Smith's most acclaimed large-scale work arrived in 2012 with Ten Freedom Summers, a four-disc oratorio for his Golden Quartet and the Southwest Chamber Music ensemble addressing the American civil rights era; it was named one of three finalists for the 2013 Pulitzer Prize for Music. He continued in that vein with America's National Parks (2016, Cuneiform), an extended work marking the National Park Service centennial performed by his Golden Quintet, and Rosa Parks: Pure Love, An Oratorio of Seven Songs (2019, TUM), which debuted at The Kitchen in New York with four ensembles, video, and butoh dance. Beginning with Tabligh (2008), Smith built a parallel relationship with the Finnish label TUM Records that produced Great Lakes Suites (2014, with Henry Threadgill, Jack DeJohnette, and John Lindberg), Celestial Weather and Ancestors (2018), and, marking his 80th birthday in 2021, a run of multi-disc box sets including Trumpet (solo), Sacred Ceremonies (a trio with Milford Graves and Bill Laswell), and The Chicago Symphonies with his Great Lakes Quartet, followed in 2022 by The Emerald Duets and String Quartets Nos. 1-12. In 2016 he also returned to ECM for the first time since Kulture Jazz, recording the duo album A Cosmic Rhythm with Each Stroke with Vijay Iyer, and in 2018 appeared as a sideman on Andrew Cyrille's ECM trio album Lebroba alongside guitarist Bill Frisell.

Smith's honors include a 2009 Guggenheim Fellowship in music composition, a 2016 Doris Duke Artist Award, and the Hammer Museum's 2016 Mohn Award for Career Achievement, which recognized both his music and his decades of work developing the Ankhrasmation notation system exhibited at the Hammer and the Renaissance Society at the University of Chicago. The Jazz Journalists Association has repeatedly honored him, including as its 2017 Musician of the Year. In 2023 he was elected to the American Academy of Arts and Letters. He has lived for many years in New Haven, Connecticut, where he has helped sustain a creative-music scene, and he remains active into his eighties, releasing Two Centuries (2022) and Fire Illuminations (2023) on Red Hook Records, Central Park's Mosaics of Reservoir, Lake, Paths and Garden (2024) with Amina Claudine Myers, and Angel Falls (2025, Intakt) among recent work, alongside a 2025 duo release with Vijay Iyer.

Smith emerged from the AACM's mid-1960s wave of experimentalism as one of its most theoretically ambitious voices, building his entire practice around Ankhrasmation, a system of rhythm-units, sound-units, improvisation-units, and symbolic-units that replaces conventional notation with graphic scores open to a performer's interpretation. His trumpet playing favors spaciousness and silence over density, using long tones, extreme dynamic control, and an unhurried sense of time that traces back to the Delta blues he heard as a boy in Mississippi as much as to the AACM's collective-improvisation ethos. Over six decades he has moved fluidly between austere solo trumpet recitals, electric ensembles indebted to Miles Davis's 1970s bands, chamber and orchestral works performed by groups including the Kronos Quartet and the California EAR Unit, and large-scale civil-rights-themed suites, while adding koto, kalimba, mbira, and the Ghanaian atenteben flute to an already wide instrumental palette. Spiritual and social themes run through much of his catalog, from Divine Love to Ten Freedom Summers and Rosa Parks: Pure Love, and his influence extends directly to younger collaborators such as pianist Vijay Iyer, who has described Smith as a formative mentor. Ten Freedom Summers' 2013 Pulitzer Prize finalist nod, alongside a Guggenheim Fellowship, a Doris Duke Artist Award, and election to the American Academy of Arts and Letters, mark him as one of the most critically honored figures to emerge from the AACM's original generation.