A family statement issued on Twitter Tuesday says Masekela passed away in Johannesburg after a lengthy battle against prostate cancer.
In a career spanning nearly six decades, Masekela gained worldwide recognition with his distinctive Afro-jazz sounds, which he played on the trumpet and also lent his vocals to.
Masekela's family described him as "a loving father, brother, grandfather and friend" who would be "forever in our hearts".
"Hugh's global and activist contribution to and participation in the areas of music, theatre, and the arts in general is contained in the minds and memory of millions across six continents and we are blessed and grateful to be part of a life and ever-expanding legacy of love, sharing and vanguard creativity that spans the time and space of six decades".
In 1977, Masekela's Soweto Blues, about the anti-apartheid Soweto uprising, was recorded by Makeba, and it reached an worldwide audience.
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He opened the 2010 FIFA Soccer World Cup Kick-Off Concert and performed at the event's opening ceremony in Johannesburg's Soccer City stadium.
Masekela cancelled all performing commitments past year because he needed all his energy to continue treatment for the cancer. He was given his first trumpet by anti-apartheid crusader Father Trevor Huddleston at age 14.
He went into exile after the 1960 Sharpeville killings in which 69 protesters were shot dead. "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. One of his most popular songs was the Mandela tribute, Bring Him Back Home.
He performed at the 1967 Monterey Pop Festival, alongside Jimi Hendrix and Janis Joplin, before releasing Grazing in the Grass in 1968, which reached number one on the pop and R&B charts. In 1964, Myriam Makeba and Masekela were married, divorcing two years later.
A charismatic horn blower and vocalist, Masekela's songs ranged from the haunting "Stimela" about trains taking black workers to South Africa's mines, to the cheeky energy of "Thanayi" about a large woman's struggle with food.