Hugh Ramapolo Masekela was born April 4, 1939, in the township of KwaGuqa in Witbank to a father who was a sculptor and the chief health inspector of Sharpeville township and a mother who was a social worker. Masekela took up playing the trumpet at the age of 14 after seeing the 1950 film Young Man with a Horn and was given his first trumpet by Archbishop Trevor Huddleston, the anti-apartheid chaplain at St. Peter's Secondary School.

Masekela quickly mastered the instrument and began to play with other aspiring musicians in the Huddleston Jazz Band – South Africa’s first youth orchestra. In 1956, he joined the African Jazz Revue that was organized by British entrepreneur, Alfred Herbert, as an African Jazz and Variety show in South Africa’s Johannesburg Windmill Theatre. In 1958, Masekela joined The Manhattan Brothers, the most popular South African singing group at the time with members including Miriam Makeba who eventually became his first wife in 1964.

Following the 1960 Sharpeville massacre, where 69 protestors were shot dead in Sharpeville by the apartheid police, Masekela moved to the United States. He attended the Manhattan School of Music in New York City, debuted his first album Trumpet Africaine in 1963, and recorded many songs including his 1968 number one hit “Grazing in the Grass." Masekela performed at the 1967 Monterey Pop Festival alongside Janis Joplin, Otis Redding, Ravi Shankar, The Who and Jimi Hendrix. 

Masekela traveled throughout Africa in the 1970s, playing in the band of popular Nigerian performer Fela Ransome-Kuti, and touring with the highlife band Hedzoleh Soundz. In the 1980s, he set up a mobile studio in Botswana, where he further developed his musical style using African mbaqanga strains. It was in 1987, Masekela released a hit single called "Bring Him Back Home" that became enormously popular and was tied to the anti-apartheid movement and the movement to free Nelson Mandela. 

Masekela was nominated for a Grammy Award three times, including a nomination for Best World Music Album for his 2012 album Jabulani, and one for Best Contemporary Pop Performance for the song "Grazing in the Grass.” Masekela joined Paul Simon’s “Graceland” world tour which featured other South African artists such as Ladysmith Black Mambazo and Miriam Makeba in the late 1980s. Masekela returned to South Africa in the early 1990s and produced music for the musical Sarafina! In June 2010, he opened the FIFA Soccer World Cup Kick-Off Concert to a global audience and performed at the event’s Opening Ceremony in Soweto’s Soccer City.