At the end of 1959, Abdullah Ibrahim, Kippie Moeketsi, Makhaya Ntshoko, Johnny Gertze and Hugh Masakela formed the Jazz Epistles, the first African jazz group to record an LP and perform to record-breaking audiences in Johannesburg and Cape Town through late 1959 to early 1960. Following the 21 March 1960 Sharpeville Massacre—where 69 peacefully protesting Africans were shot dead in Sharpeville, and the South African government banned gatherings of ten or more people—and the increased brutality of the Apartheid state, Masekela left the country. 

Masekela 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. During that period, Masekela visited the United States, where he was befriended by Harry Belafonte. He attended Manhattan School of Music in New York, where he studied classical trumpet from 1960 to 1964.

He had hits in the United States with the pop jazz tunes "Up, Up and Away" (1967) and the number-one smash "Grazing in the Grass" (1968), which sold four million copies.He also appeared at the Monterey Pop Festival in 1967.

He has played primarily in jazz ensembles, with guest appearances on recordings by The Byrds and Paul Simon. In the 1980s, he toured with Paul Simon in support of Simon's album Graceland.  In 1990 Hugh returned home, following the unbanning of the ANC and the release of Nelson Mandela – an event anticipated in Hugh’s anti-apartheid anthem ‘Bring Home Nelson Mandela’ (1986) which had been a rallying cry around the world.