He was the son of a successful Congolese businessman and was born in Musumba, Congo. He received his education from an American missionary school and later trained as an accountant. In the 1950s, he took over a chain of stores in Katanga province and became involved in politics, founding the CONAKAT party which ran under a banner of an independent, federal Congo.
In the general elections of 1960, CONAKAT won control of the Katanga provincial legislature. That same year, the Congo became an independent republic, and in the resulting strife, Tshombe and CONAKAT declared Katanga's secession from the rest of the Congo. See Congo Crisis.
The Christian, anti-communist, pro-Western Tshombe was elected president of Katanga in August 1960, and declared that "we are seceding from chaos." Favoring continued ties with Belgium, Tshombe asked the Belgian government to send military officers to recruit and train a Katangese army. The Congolese Prime Minister Patrice Lumumba and his successor Cyrille Adoula requested intervention from United Nations forces, which they received. Patrice Lumumba was later abducted, taken to Katanga and assassinated with the collusion of the Belgian authorities. It took the United Nations two years to force Katanga to submit to Congolese rule.
In 1963, UN forces succeeded in capturing Katanga, driving Tshombe into exile in Northern Rhodesia, later to Spain. In 1964 he returned to the Congo to serve as prime minister in a new Coalition government, but was dismissed from his position the following year by President Joseph Kasa Vubu. In 1966, Prime Minister Joseph Mobutu, who had staged a successful coup against President Kasa Vubu a year earlier, brought charges of treason against Tshombe, who again fled the country, and settled in Spain.
In 1967, he was sentenced to death in absentia. On June 30, 1967, a plane he was traveling in was hijacked to Algeria, where he was first jailed and then kept under house arrest until his death from heart failure in 1969.
These rumors were the basis for Daniel Carney's book that later became the 1978 film The Wild Geese, which starred Richard Burton. In the film, Winston Ntshona plays a respected, deposed African president who is imprisoned following the hijacking of his plane.