Elected to the House of Commons in 1929, and then called up to the House of Lords by a writ of acceleration in 1941, before he succeeded his father as Marquess of Salisbury in 1947.

Lord Salisbury was a prominent Tory politician in the 1940s and 1950s, serving in the governments of Winston Churchill, Anthony Eden, and Harold Macmillan. He was known as a hardline imperialist. In 1952, as Secretary of State for Commonwealth Relations, he tried to make permanent the exile of Seretse Khama, kgosi of the Bamangwato people in Bechuanaland, for marrying a white British woman. During the 1960s, Lord Salisbury continued to be a staunch defender of the white-dominated governments in South Africa and in Southern Rhodesia (now Zimbabwe).

He was also a fierce opponent of liberal-left attempts to reform the House of Lords, yet he created what is known as the Salisbury Convention. In 1961 he became the first president of the Conservative Monday Club, a post he held until his death.

Lord Salisbury was married to Elizabeth Vere Cavendish, a cousin of the 10th Duke of Devonshire and a great-granddaughter of the 7th Duke of Devonshire and his wife, herself a granddaughter of Georgiana, Duchess of Devonshire. They had three sons, of whom only the eldest survived the Second World War.