Cecil was the third son of the 3rd marquess of Salisbury, who was three times British prime minister. During World War I, Cecil was successively undersecretary of state for foreign affairs, minister of blockade, and assistant secretary of state for foreign affairs. As early as 1916 he began to draw up an international peacekeeping agreement, and in 1919, when he was sent to the peace conference in Paris, his ideas proved generally compatible with those of United States President Woodrow Wilson and South African Field Marshal Jan Christian Smuts, the other prominent advocates of the League. Like Smuts, Lord Robert believed in a world order determined by the white nations; he successfully opposed a provision for absolute racial equality among League member states.

As the principal British delegate to the disarmament conference at Geneva (1926–27), Cecil disagreed with the instructions given him and resigned from Prime Minister Stanley Baldwin's government. During the 1930s he unsuccessfully argued for League measures against aggression by Japan in Manchuria and by Italy in Ethiopia. He was one of the few in Parliament to vote against the concessions made to Nazi Germany at Munich in 1938.