From 1887 to 1906, Cecil practised civil law, including work in Chancery and parliamentary practice. On 15 June 1899, he was appointed as a Queen's Counsel (QC). He also collaborated in writing a book, entitled Principles of Commercial Law.
Fifty years old at the outbreak of World War I and too old for military service, Cecil went to work for the Red Cross. Following the formation of the 1915 coalition government, he became Under-Secretary of State for Foreign Affairs on 30 May 1915. He served in this post until 10 January 1919, additionally serving in the cabinet as Minister of Blockade between 23 February 1916 and 18 July 1918. He was responsible for devising procedures to bring economic and commercial pressure against the enemy.
On 25 May 1923, Cecil returned to the cabinet as Lord Privy Seal, a position held by several members of his family. He did not stand again in the general election of December 1923 and, after the Conservatives lost their majority, he was created Viscount Cecil of Chelwood, of East Grinstead in the County of Sussex on 28 December 1923. He remained Lord Privy Seal until 22 February 1924, when Ramsey MacDonald's minority Labour cabinet took office.
From the inception of the League, after World War I, to its demise in 1946, Cecil's public life was almost totally devoted to the League. At the Paris Peace Conference, he was the British representative in charge of negotiations for a League of Nations; from 1920 until 1922, he represented the Dominion of South Africa in the League Assembly; in 1923 he made a five-week tour of the United States, explaining the League to American audiences. In the Conservative administrations of 1923 to 1924, and 1924 to 1927 he was the minister responsible, under the jurisdiction of the Foreign Secretary, for British activities in League affairs.
During a naval conference of 1927 in Geneva, negotiations broke down after the United States refused to agree to the British argument that Britain needed a minimum of seventy cruisers to adequately defend the British Empire and its trade and communications. The cutting of British cruisers to fifty from seventy was proposed by the Americans in return for concessions over the size of cruisers and the calibre of their guns. Cecil was part of the British delegation at Geneva and resigned from the cabinet because the British government let the conference break down rather than reduce the number of Britain's cruisers.
Although an official delegate to the League as late as 1932, Cecil worked independently to mobilise public opinion in support of the League. He was president of the British League of Nations Union from 1923 to 1945, and joint founder and president, with a French Jurist, of the International Peace Campaign, known in France as Rassemblement universel pour la paix. Among his publications during this period were The Way of Peace (1928), a collection of lectures on the League; A Great Experiment (1941), a personalised account of his relationship to the League of Nations; and All the Way (1949), a more complete autobiography.
In the spring of 1946, he participated in the final meetings of the League at Geneva, ending his speech with the sentence: "The League is dead; long live the United Nations!" He lived for thirteen more years, occasionally occupying his place in the House of Lords, and supporting international efforts for peace through his honorary life presidency of the United Nations Association.