G. V. Desani was born in Nairobi, Kenya, where his parents were working as wood merchants. The family returned to Karachi in 1914, where Desani was educated. He arrived in Britain at the age of 17, to escape from an arranged marriage. When he arrived in England in 1926, he was befriended by George Lansbury, who helped him acquire a reader's pass to the British Museum Reading Room. During this period he also found work as an actor in films. Furthermore, he worked as a foreign corespondent for a number of Indian newspapers and news agencies, such as the Associated Press, Reuters and The Times of India. He returned to India in 1928, touring Rajasthan, on which he subsequently lectured extensively for the Bombay, Baroda and Central India Railway Company.

Desani returned to Britain in the summer of 1939, only weeks before the outbreak of the Second World War.  He continued to work as a writer, journalist, and broadcaster for the Indian Section of the BBC Eastern Service and the Home Division. Desani broadcast both in Hindustani and in English and was praised for his wit, humour and ability as a script-writer. He also acted in radio plays. Furthermore, Desani lectured for the Ministry of Information and the Imperial Institute, regularly touring the regions and speaking to soldiers, schools and university colleges. These lectures featured as one of his Talks Programmes in Hindustani, titled 'My Lecture Tours' (broadcast 8 May 1943). They were widely praised and drew large audiences.

During this period, he wrote his best known work of fiction, the experimental novel All About Mr. Hatterr (later republished and revised as All About H. Hatterr). On publication the book was very well received by critics. For example, T. S. Eliot praised it as a remarkably original book: 'It is amazing that anyone should be able to sustain a piece of work in this style and tempo and at such length'. The critic C. E. M. Joad compared the book to 'Joyce and Miller with a difference: the difference being due to a dash of Munchhausen and the Arabian Nights'.  With its inventive use of language and its endorsement of hybridity, the work is a trailblazer for the fiction of Salman Rushdie, who has acknowledged its influence.

While in England, Desani also published his ‘poetic play’ Hali, as well as short fiction, sketches and essays. Shortly after the publication of Hali, Desani left Britain and returned to India. He was offered a position as cultural ambassador for Jawaharlal Nehru, however he did not take this up. In 1959 he travelled to Burma to study Buddhist and Hindu culture. During the 1950s and 1960 he wrote a regular column, 'Very High, Very Low', as well as articles for The Times of India and Illustrated Weekly of India. In 1967 he was appointed Professor of Philosophy at the University of Texas, Austin, a position he held until his retirement in 1978. He spent the final years of his life in Dallas.