He quickly became an integral part of the 1950s jazz scene in Johannesburg as a member of the band the Jazz Epistles and a member of the orchestra in the groundbreaking jazz opera, "King Kong".
He left South Africa following a bloody attack on African protesters in Sharpeville to fight for South African freedom from the outside.
"Some of us have followed his music right from when he came to record with Hedzoleh Soundz group who were based at Napoleon Club owned by the late Faisal Helwani...they came out with an album titled "The Boy's Doin" It'", Uncle Ken fondly recalled.
Masekela's family on Tuesday released a statement confirming the death of the veteran trumpeter, who was diagnosed with prostate cancer in 2008.
Later, after writing the seminal anti-apartheid protest anthem, Bring Him Back Home (Nelson Mandela), he would return to NY once again, in the late 1980s, to craft the music for the stage production Sarafina! He scored an global number one hit in 1968 with "Grazing In The Grass".
"Even in recent years, "Bra Hugh" continued to fly the flag for South Africa in worldwide festivals, and his home country including the performance at the Grammy Awards in 2013", Minister Mthethwa said.
He was also considered the star performer at the Graceland concert in Hyde Park, London, 2012 when he joined Paul Simon on stage and won an ovation from the crowd.
In 1990 Masekela returned home, following the unbanning of the ANC and the release of Mandela. He said another tumor was then discovered and he had surgery.
Condolences from fans poured out Tuesday on social media paying tribute to the influential musician's career.
In this way, his remarkable body of work - one that spans 44 albums and countless collaborations and live performances - is folk music of the kind produced by the likes of Public Enemy, Cab Calloway, Van Morrison or Dizzy Gillespie. "His contribution to the struggle for liberation will never be forgotten", said Zuma.
It is with sadness that we received the news of the passing of world-renowned music legend and political struggle icon Dr Hugh Masekela.
With encouragement from the globally renowned South African-born protest singer Miriam Makeba, his wife in the mid-1960s, he also lent his baritone voice to songs in Zulu, Xhosa and English.
Hugh Masekela, the South Africa jazz legend dies at 78.