Sassoon, having matured greatly as a result of his military service, continued to seek emotional fulfilment, initially in a succession of love affairs with men, including the landscape architectural and figure painter, draftsman and illustrator, William Park "Gabriel" Atkin, actor Ivor Novello; Novello's former lover, the actor Glen Byam Shaw; German aristocrat Prince Philipp of Hesse; the writer Beverley Nichols; an effete aristocrat, the Hon. Stephen Tennant. Only the last of these made a permanent impression, though Shaw remained his close friend throughout his life.
In September 1931, Sassoon rented and began to live at Fitz House, Teffont Magna, Wiltshire. In December 1933, to many people's surprise, he married Hester Gatty, who was many years his junior; this led to the birth of a child, something which he had long craved. This only child George (1936–2006), became a scientist, linguist and author, and was adored by Siegfried, who wrote several poems addressed to him. However, the marriage broke down after the Second World War, Sassoon apparently unable to find a compromise between the solitude he enjoyed and the companionship he craved.
Separated from his wife in 1945, Sassoon lived in seclusion at Heytesbury in Wiltshire, although he maintained contact with a circle which included E M Forster and J R Ackerley. One of his closest friends was the young cricketer Dennis Silk. He formed a close friendship with Vivien Hancock, headmistress of Greenways School at Ashton Gifford, which his son George attended. The relationship provoked Hester to make some strong accusations against Vivien Hancock, who responded with the threat of legal action.
Sassoon was appointed Commander of the Order of the British Empire in the 1951 New Year Honours. Towards the end of his life, he converted to Roman Catholicism. He had hoped that Ronald Knox, a Roman Catholic priest and writer whom he admired, would instruct him in the faith, but Knox was too ill to do so. The priest Sebastian Moore was chosen to instruct him instead, and Sassoon was admitted to the faith at Downside Abbey, close to his home. He also paid regular visits to the nuns at Stanbrook Abbey, and the abbey press printed commemorative editions of some of his poems. During this time he also became interested in the supernatural, and joined the Ghost Club.
Siegfried Sassoon died one week before his 81st birthday, of stomach cancer, and is buried at St Andrew's Church, Mells, Somerset, close to Ronald Knox.