Ambrose Olusiji Akinmusire was born on May 1, 1982, and grew up in Oakland, California. As a student in the Berkeley High School Jazz Ensemble he caught the attention of saxophonist Steve Coleman when Coleman visited the school to lead a workshop, and Coleman later hired him for a European tour with his band Five Elements. He also played in the Monterey Jazz Festival's Next Generation Jazz Orchestra. His own website says he took in concerts by the Art Ensemble of Chicago and Ellis Marsalis Jr. as a young person in Oakland, and names Roy Hargrove as an example of a trumpeter who moved freely across genres.

Akinmusire studied at the Manhattan School of Music in New York, then returned to California for a master's degree at the University of Southern California and a place at the Thelonious Monk Institute of Jazz (now the Herbie Hancock Institute of Jazz Performance) in Los Angeles. In 2007 he won both the Thelonious Monk International Jazz Competition and the Carmine Caruso International Jazz Trumpet Solo Competition. His debut album, Prelude... to Cora, came out on the Spanish label Fresh Sound New Talent in 2008 and is dedicated to his mother, Cora; he wrote all but three of its tracks, the exceptions including Benny Golson's "Stablemates." Back in New York he worked with Vijay Iyer, Aaron Parks, Esperanza Spalding, and the pianist Jason Moran, and took part in Moran's multimedia concert event In My Mind: Monk at Town Hall, 1957. It was around then that Bruce Lundvall, president of Blue Note Records, noticed him.

His Blue Note debut, When the Heart Emerges Glistening (released April 5, 2011), was produced by Moran and recorded on September 20 to 22, 2010, with tenor saxophonist Walter Smith III, pianist Gerald Clayton, bassist Harish Raghavan, and drummer Justin Brown; Lundvall contributed a letter of praise to the booklet. DownBeat's critics named him Jazz Artist of the Year in 2011 and voted him top trumpeter every year from 2013 through 2020. The Imagined Savior Is Far Easier to Paint (2014), a self-produced 79-minute set of 13 tracks, added a string quartet and guest singers Becca Stevens, Theo Bleckmann and Cold Specks, and its "Rollcall for Those Absent" reads out the names of young people killed by gunfire. That year he received the North Sea Jazz Festival's Paul Acket Award and a Doris Duke Impact Award, followed by a Doris Duke Artist Award in 2015. He is also the featured trumpeter on the last track of Kendrick Lamar's 2015 album To Pimp a Butterfly.

A Rift in Decorum: Live at the Village Vanguard (June 9, 2017) captured his quartet of pianist Sam Harris, Raghavan and Brown on a two-disc set of newly written pieces. Origami Harvest (October 12, 2018) was commissioned by curators Judd Greenstein of the Ecstatic Music Festival and Kate Nordstrum of the Liquid Music Series, and joins his trumpet and keyboards, Harris, drummer Marcus Gilmore, the Mivos Quartet, and the poet and rapper Kool A.D.; it made The New York Times' list of the best jazz of 2018. On the Tender Spot of Every Calloused Moment (June 5, 2020) reunited the Harris, Raghavan and Brown quartet and was nominated for the Grammy Award for Best Jazz Instrumental Album. The title refers to a 2016 visit to an Oakland transformed by gentrification.

His Nonesuch debut, Owl Song (December 15, 2023), was recorded March 7 and 8, 2022, at 25th Street Recording Studio in Oakland. It is a spare trio date with guitarist Bill Frisell and drummer Herlin Riley, and it earned a Best Jazz Instrumental Album nomination at the Grammys held in 2025. Earlier that year came Beauty Is Enough (June 23, 2023), sixteen short solo trumpet pieces on his own Origami Harvest label. honey from a winter stone (January 31, 2025), a five-track self-portrait recorded in Minneapolis on May 21, 2023, with singer Kokayi, Harris, Brown, and the Mivos Quartet, was nominated for Best Alternative Jazz Album at the 2026 Grammys. In 2025 he also appeared as an equal-billed partner on bassist Linda Oh's trio album Strange Heavens, with drummer Tyshawn Sorey, and on June 12, 2026, Nonesuch released Slo-Mo Neon Luminate Hoverings, a duo album with guitarist Mary Halvorson, whom he has played with informally since 2009. Grammy.com lists four nominations for him, none of them yet a win.

He was named artistic director of the Herbie Hancock Institute of Jazz Performance in 2023, and Stanford University's music department lists him as its Director of Jazz and Associate Professor of Music. In 2026 he was named one of the ten winners of the Chanel Next Prize, and on August 20, 2026, he was the trumpet soloist at the BBC Proms centenary concert for Miles Davis at London's Royal Albert Hall, with the BBC Concert Orchestra and conductor Miho Hazama.

Akinmusire is often classed as an avant-garde jazz trumpeter, and critics have singled out his wide-ranging upper register, his patient, slowly developing solo lines, and a penetrating tone. His writing often carries a stated social subject: names of people killed by police or gunfire on The Imagined Savior Is Far Easier to Paint and Origami Harvest, gentrification on On the Tender Spot of Every Calloused Moment, colorism and erasure on honey from a winter stone. His albums move between small-group post-bop, string-quartet writing, spoken word and hip-hop, and, on Owl Song and the Halvorson duo, unhurried near-silence. His website points to Steve Coleman as the first major bandleader to take him on, and he has named Booker Little among his influences. A Guardian reviewer heard the trumpet-and-tenor interplay on the Blue Note debut as an updated version of the Miles Davis and Wayne Shorter partnership, and Origami Harvest has been called his most adventurous record. His trumpet teaching draws on the methods of Laurie Frink, according to Stanford's faculty page. He has also been a regular in critics' polls: DownBeat's critics have named him top trumpeter every year from 2013 through 2020.