The eldest son of William, 2nd Duke of Portland (whom he succeeded in 1762), he was educated at Westminster and Christ Church, Oxford. In 1761 he entered Parliament and from July 1765 to December 1766 was lord chamberlain of the household. Appointed by the then prime minister, Charles Watson-Wentworth, 2nd Marquess of Rockingham, Portland served briefly (April–August 1782) as lord lieutenant of Ireland. On the fall of the ministry of Lord Shelburne (afterward 1st Marquess of Lansdowne) in 1783, Portland was selected by Lord North and Charles James Fox as titular chief of their coalition government, in which North was home secretary and Fox foreign secretary. Portland was dismissed after the House of Lords, at the insistence of King George III, rejected Fox's reform bill for India.

As home secretary (1794–1801) in the first administration of William Pitt the Younger, Portland, despite the British fear of subversion while Great Britain was at war with Revolutionary France, distinguished himself by his restraint in applying arbitrary laws against sedition and treason. He nevertheless suppressed the Irish Rebellion of 1798. Later (1801–05) he was lord president of the council. His second ministry was dominated by the foreign secretary, George Canning, and the secretary for war and the colonies, Viscount Castlereagh (afterward 2nd Marquess of Londonderry). Their disagreements (culminating in a duel) and Portland's ill health caused him to resign shortly before his death.