On 12 June 1931, Clarke was married to Frances Mary Powys Sketchley, a daughter of Maj. Frederick Powys Sketchley.[7] They divorced in 1936.[4]
On 1 September 1938, he married Elisabeth Irene (née Cook) Campbell, the daughter of Dr. William Alexander Cook of Tulsa, Oklahoma and former wife of Colin Leiter Campbell. They were the parents of:[8]
He married, thirdly, Constance Elizabeth (née Gibbs) Langton, daughter of Herbert Gray Gibbs, on 11 February 1947. She was previously married to John Stephen Langton. Before their divorce in 1953, they were the parents of:[4]
Orme Roosevelt Clarke (1947–1992), who married Joanna Valentine Schuster, daughter of Maj. John Schuster and Hon. Lorna Frances Hermon-Hodge (a daughter of Roland Hermon-Hodge, 2nd Baron Wyfold), in 1971. They divorced in 1989 and he married Christine V. O'Flaherty, daughter of J. G. O'Flaherty, in 1991.[4]
Sir Humphrey committed suicide by shotgun on 22 January 1973, at the age of 66, at his estate in Bibury, Gloucestershire.[5] He left an estate valued at £786,274,[10] was succeeded in the baronetcy by his eldest son, Toby.[4]