Mulatu Astatke was born December 19, 1943, in Jimma, in what was then the Ethiopian Empire. In 1959, at age sixteen, he was sent to Britain for his education, initially toward an engineering career, and enrolled at Lindisfarne College near Wrexham, Wales. Music took over: he studied piano, clarinet, and harmony at Trinity College of Music in London, and by the early 1960s was working the Soho club circuit alongside African and Caribbean musicians, including a stint with bandleader Edmundo Ros's orchestra and singer Frank Holder. In 1963 he enrolled at Berklee College of Music in Boston, the school's first African student, concentrating on vibraphone and percussion.

His recording career started in New York rather than Ethiopia. In 1966 he cut Afro-Latin Soul, Volumes 1 & 2 for the small Worthy Records label, a quartet date built around Latin percussion (congas, timbales) under his vibraphone, alongside pianist/trumpeter Rudy Houston and bassist Robert Cuadrado. He returned to Addis Ababa at the end of the decade and began developing the hybrid he named "Ethio-jazz": Ethiopian pentatonic modes carried by jazz harmony and Latin-derived rhythm sections, with vibraphone, congas, and bongos, none of them previously part of Ethiopian popular music, at the center of the sound. Through the early 1970s he became the connective figure of Addis Ababa's "Swinging Addis" scene, arranging and playing on records for the era's leading vocalists, including Mahmoud Ahmed, Alemayehu Eshete, Tilahun Gessesse, and Getatchew Mekurya, most of it released on Amha Eshete's Amha Records, Ethiopia's first independent label. He returned to New York in 1972 to record the solo album Mulatu of Ethiopia, and in 1973 performed alongside Duke Ellington during a U.S. State Department-sponsored tour of Ethiopia, in a concert attended by Emperor Haile Selassie. His 1974 Amha Records LP Yekatit Ethio-Jazz is often cited as the first Ethiopian album conceived as a single unified work rather than a collection of singles.

Ethiopia's 1974 revolution and the Derg military dictatorship that followed curtailed the country's nightlife and recording industry for years, and Astatke's international profile went dormant even as he kept working at home, including vibraphone on Hailu Mergia and the Walias Band's 1977 album Tche Belew. His rediscovery abroad began in 1998, when the Paris-based label Buda Musique launched its Éthiopiques reissue series and devoted its fourth volume entirely to him: Éthiopiques 4: Ethio Jazz & Musique Instrumentale, 1969-1974. That reissue, and the ones that followed, introduced Ethio-jazz to a new generation of listeners and sample-hunting producers. In 2005, seven of his compositions scored Jim Jarmusch's film Broken Flowers, starring Bill Murray, exposing his music to a far larger audience than any prior release had reached. The following years brought a run of new collaborations: a 2004 tour and 2006 live album with the Boston big band Either/Orchestra (Éthiopiques 20: Live in Addis, recorded at the Ethiopian Music Festival in Addis Ababa), a 2008 Radcliffe Institute fellowship and artist residency at Harvard and MIT, and the 2009 studio pairing Inspiration Information, Vol. 3 with the London funk-jazz group the Heliocentrics.

Astatke kept recording and touring into his eighth decade. Sketches of Ethiopia (2013, Jazz Village) was his first internationally distributed studio album, built around traditional Ethiopian instruments, the washint flute, krar lyre, and masinko fiddle, set against a jazz rhythm section, and reached number 24 on the UK's Jazz & Blues chart. He collaborated repeatedly with the Melbourne group Black Jesus Experience on Cradle of Humanity (2016) and To Know Without Knowing (2019), received an honorary doctorate from Berklee in 2012, and was made a Chevalier of France's Ordre des Arts et des Lettres in September 2019. In 2023 the Tel Aviv Afrobeat collective Hoodna Afrobeat Orchestra, co-founded by drummer Matan Assayag, invited him to Israel to record together; the resulting album, Tension, produced by Neal Sugarman of the Dap-Kings and Daptone Records, was released November 8, 2024, on the UK label Batov Records, one credit among the dozens of international collaborations of his later career rather than a departure from it. In 2025 he released Mulatu Plays Mulatu (Strut), his first major studio album in over a decade, recorded between London and Addis Ababa with producer Dexter Story, and announced a farewell tour that closed with two sold-out concerts at London's Royal Festival Hall that November, a month before his 82nd birthday. He remains active into 2026, with further festival dates scheduled.

Astatke's core achievement was inventing a genre rather than mastering an existing one: Ethio-jazz layers the five-note qenet scales of Ethiopian traditional music over jazz chord voicings and Latin-jazz rhythm patterns, an idea he arrived at through his parallel training in Ethiopian music, the Afro-Cuban and Latin jazz he encountered in New York and Boston, and Western jazz harmony. He was the first musician to bring vibraphone, congas, and bongos into Ethiopian popular music, and functioned as much as an arranger and bandleader, shaping other vocalists' recordings for Amha Records, as he did a performer on his own dates. Critics and reissue labels have since treated him as the central figure of the "Swinging Addis" era his own studio and arranging work helped define, and his instrumentals have proven unusually durable outside jazz circles: they have been sampled by Nas and Damian "Jr. Gong" Marley, Kanye West, Cut Chemist, Quantic, Madlib, and Oddisee, and used prominently in Jim Jarmusch's Broken Flowers (2005) and, decades later, in the closing credits of Nickel Boys (2024).