[4][5] Huddleston asked the leader of the then Johannesburg "Native" Municipal Brass Band, Uncle Sauda, to teach Masekela the rudiments of trumpet playing.

Soon, some of his schoolmates also became interested in playing instruments, leading to the formation of the Huddleston Jazz Band, South Africa's first youth orchestra.

[8][9] Following a Manhattan Brothers tour of South Africa in 1958, Masekela joined the orchestra of the musical King Kong, written by Todd Matshikiza.

[10] King Kong was South Africa's first blockbuster theatrical success, touring the country for a sold-out year with Miriam Makeba and the Manhattan Brothers' Nathan Mdledle in the lead.

He was helped by Trevor Huddleston and international friends such as Yehudi Menuhin and John Dankworth, who got him admitted into London's Guildhall School of Music in 1960.

[15] After securing a scholarship back in London,[2] Masekela moved to the United States to attend the Manhattan School of Music in New York, where he studied classical trumpet from 1960 to 1964.

In 1974, Masekela and friend Stewart Levine organised the Zaire 74 music festival in Kinshasa set around the Rumble in the Jungle boxing match.

[18] He played primarily in jazz ensembles, with guest appearances on recordings by the Byrds ("So You Want to Be a Rock 'n' Roll Star" and "Lady Friend") (the latter being denied by David Crosby) and Paul Simon ("Further to Fly").

[23][24] The event, still in existence, continues as the annual Botswana Music Camp, giving local musicians of all ages and from all backgrounds the opportunity to play and perform together.

[33] He also provided interpretations of songs composed by Jorge Ben, Antônio Carlos Jobim, Caiphus Semenya, Jonas Gwangwa, Dorothy Masuka, and Fela Kuti.

In 2006 Masekela was described by Michael A. Gomez, professor of history and Middle Eastern and Islamic studies at New York University as "the father of African jazz.

The series, called Umlando – Through My Father's Eyes, was aired in 10 parts during ESPN's coverage of the FIFA World Cup in South Africa.

[39] In 2016, at Emperors Palace, Johannesburg, Masekela and Abdullah Ibrahim performed together for the first time in 60 years, reuniting the Jazz Epistles in commemoration of the 40th anniversary of the historic 16 June 1976 youth demonstrations.

[40][41][42] Masekela was involved in several social initiatives, and served as a director on the board of the Lunchbox Fund, a non-profit organization that provides a daily meal to students of township schools in Soweto.