Masekela soon became part of the Huddleston Jazz Band.
By the mid-1950s, he joined the Alfred Herbet's African Jazz Revue and began creating his signature "Afro-Jazz" sound.
In 1960, at the age of 21, as he was coming under pressure from authorities for his anti-apartheid activities, he decided to leave his home country for England.
Once in London, his then-girlfriend and future wife, singer Miriam Makeba, encouraged him to come to the U.S., where she had arrived the previous year.
"We'd always dreamt of coming to the States, but she came a year earlier and blew the States away," he told NPR.
"So she said, 'Hey, you got to come, forget about London, this is the place to be.' And, she was on a first name basis with everybody. Then she and Harry Belafonte gave me a scholarship to Manhattan School of Music. I also had to work part-time in Harry Belafonte's music publishing, because they ain't going to give you no money," Masekela said.
In addition to Belafonte, he also worked with legends Louis Armstrong and Miles Davis. Along with Miriam, they all encouraged him to develop his own style.
"[They] said, `Listen, if you're going to play jazz, you're just going to be a statistic like all of us. Why don't you infuse some of the stuff from your home into your music, and then maybe you'll come up with something that will interest everybody and that we can learn from.' And I guess I came up with some kind of a hybrid," Masekela told NPR.
In 1962, he released his first album, Trumpet Africaine.
Makeba and Masekela wed in 1964, but their marriage lasted a scant two years. Even so, the two remained friends.
In 1967, the year of his hit Up, Up and Away, he also performed alongside Janis Joplin, Otis Redding, Ravi Shankar, The Who and Jimi Hendrix at the Monterey Pop Festival. A year later, he performed on Grazing in the Grass, which hit U.S. charts and went on to become a global hit.
In 1977, Masekela's Soweto Blues, about the anti-apartheid Soweto uprising, was recorded by Makeba, and it reached an international audience.
He penned the anti-apartheid anthem Bring Home Nelson Mandela in 1986 and returned to his native South Africa following Mandela's release.
In 1987, he appeared with Paul Simon on his Graceland album tour alongside South African musicians Ladysmith Black Mambazo and again in 2012 on the 25th anniversary of the Grammy-award winning album's release.
In 1997, he acknowledged that he had become addicted to alcohol and drugs, and checked himself into a recovery center in England.
Masekela performed at the opening ceremony of the FIFA World Cup and tournament in Soweto's Soccer City in 2010.
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CorrectionJan. 23, 2018
A previous version of this post incorrectly referred to a band as Ladyship Black Mambozo; the band's name is Ladysmith Black Mambazo.