Masekela was born in in Kwa-Guqa Township, Witbank, South Africa. He began singing and playing piano as a child. At age 14, after seeing the film Young Man with a Horn (in which Kirk Douglas plays a character modeled after American jazz cornetist Bix Beiderbecke), he took up playing the trumpet. His first trumpet was given to him by Archbishop Trevor Huddleston, the anti-apartheidchaplain at St. Peter's Secondary School.
Huddleston asked the leader of the then Johannesburg "Native" Municipal Brass Band, Uncle Sauda, to teach Masekela the rudiments of trumpet playing. Masekela quickly mastered the instrument. Soon, some of his schoolmates also became interested in playing instruments, leading to the formation of the Huddleston Jazz Band, South Africa's first youth orchestra. By 1956, after leading other ensembles, Masekela joined Alfred Herbert's African Jazz Revue.
Since 1954, Masekela has played music that closely reflects his life experience. The agony, conflict, and exploitation South Africa faced during the 1950s and 1960s: This inspired, influenced him to make music and also spread political change. He was an artist who in his music vividly portrayed the struggles and sorrows, as well as the joys and passions of his country. His music protested about apartheid, slavery, government; the hardships individuals were living. Masekela reached a large population that also felt oppressed due to the country's situation.
Following a Manhattan Brothers tour of South Africa in 1958, Masekela wound up in the orchestra of the musical King Kong, written by Todd Matshikiza. King Kong was South Africa's first blockbuster theatrical success, touring the country for a sold-out year with Miriam Makeba and the Manhattan Brothers' Nathan Mdledle in the lead. The musical later went to London's West End for two years.