Sekoto was born on 9 December 1913 at the Lutheran Mission Station in Botshabelo, near Middelburg, Eastern Transvaal (now known as Mpumalanga). He was the son of Andreas Sekoto, a leading member of the new Christian converts. Sekoto was schooled at Wonderhoek, which was established by his father, a priest and teacher. As the son of a missionary, he experienced music as a part of his life and was introduced to the family harmonium at an early age.

In 1938 at the age of 25 he left for Johannesburg to pursue a career as an artist. He lived with relatives in Gerty Street, Sophiatown. He held his first solo exhibition in 1939. In 1940 the Johannesburg Art Gallery purchased one of his pictures; it was to be the first picture painted by a black artist to enter a museum collection. In 1942 he moved to District Six in Cape Town, where he lived with the Manuel family. Here he apparently met George Pemba (1912–2001), (qv.) who was visiting from Port Elizabeth. In 1945 he moved to Eastwood, Pretoria. During this time, Sekoto lived with his mother, stepfather, and brother. It has been said that some of Sekoto’s most beloved work is from this time, and has been deemed ”the golden years of his art”. The reason being that this was the last body of work he completed in South Africa, before going to Paris.

In 1947 he left South Africa to live in Paris under self-imposed exile. It is said that when Sekoto departed from South Africa, the people that were familiar with his work felt a great loss from him leaving. The first years in Paris were hard, and Sekoto was employed as a pianist purely by chance at l’Echelle de Jacob (“Jacob’s ladder”), a trendy nightclub that had reopened for business after World War II. Here he played jazz and sang “Negro spirituals”, popular French songs of the period and some Harry Belafonte. Music became the way that he could pay his living and art school expenses.

Between 1956 and 1960, several of Sekoto’s compositions were published by Les Editions Musicales. Sekoto played piano and sang on several records. He composed 29 songs, mostly excessively poignant, recalling the loneliness of exile, yet displaying the inordinate courage of someone battling to survive in a foreign cultural environment. In 1966 he visited Senegal for a year.

Sekoto’s paintings became political in the 1970s due to apartheid in his home country. In 1989 the Johannesburg Art Gallery honoured him with a retrospective exhibition and the University of Witwatersrand with an honorary doctorate. He died on 20 March 1993 at a retirement home outside Paris.