Cloete was born in Paris, France to a French mother and South African father. He was educated at Lancing College, and the school gives out a yearly prize in his honour to a student who excels in literature and creative writing. He lived most of his adult life in the town of Hermanus, in the Western Cape. He published his first novel, Turning Wheels, in 1937: it became a best-seller, selling more than two million copies. Importation of the book was subsequently banned in South Africa, owing to its commentary on the Great Trek, the event in which the book is set.
Many of his 14 novels and most of his short stories are historically based fictional adventures, set against the backdrop of major African, and, in particular, South African historical events. Apart from Turning Wheels, another prominent novel, 1963's Rags of Glory, is set during the Boer war (with, according to its foreword, much of the historical information based on Rayne Kruger's Goodbye Dolly Gray.) Two of his novels were turned into movies: The Fiercest Heart (1961) is based on his 1955 novel of the same name, and Majuba, released in 1968, is based on his 1941 novel The Hill of the Doves.
His short stories are also much-acclaimed. He published at least eight volumes in his lifetime.
In addition to producing South-African related works, Cloete was among the pioneers of the by-now voluminous literary sub-genre depicting the aftermath of nuclear war. His 1947 novelette The Blast is written as the diary of a survivor living in the ruins of New York (published in 6 Great Short Novels of Science Fiction, ed. Groff Conklin, 1954).
Other written genres to which he contributed included poetry (collected in a volume published in 1941, The Young Men and the Old) and biography (African Portraits, 1946).
He published the first part of his autobiography, A Victorian Son, in 1972 and the second, The Gambler, in 1973. Stuart Cloete died on 19 March 1976, in Cape Town, South Africa.
Following Cloete's death, the copyright to his works passed to his widow, Tiny Cloete. After her death in August, 1993, the copyright passed to Cloete's American-South African friend Warren Wilmot Williams. Although Cloete never wished to have any children of his own, he regarded Williams as an "adopted" son. In the late 1960s Cloete was instrumental in launching the young Williams' career as a documentary film producer and media executive. After inheriting the Stuart Cloete literary estate, Warren Williams established a trust to hold the copyright to Cloete's works. The copyright is managed by the British-based company Stuart Cloete Print Holdings Ltd.