He succeeded to his father's title of marquess in 1750 and served from 1751 to 1762 as gentleman of the bedchamber for George II (reigned 1727–60) and George III (reigned 1760–1820). In July 1765 George III dismissed George Grenville as head of the ministry and appointed Rockingham in his place. The new prime minister obtained repeal of the Stamp Act, which had imposed an unpopular tax on the American colonists, but he agreed to the passage of a Declaratory Act reaffirming Parliament's power to tax the colonies and to make statutes binding on them in all areas. He tried to lighten the tax burden on Americans by reducing the duty on non-British imported molasses. Despite solid legislative achievements in other areas, Rockingham's ministry collapsed through internal dissension, and in July 1766 George replaced Rockingham with William Pitt (later earl of Chatham).

For the next 16 years Rockingham led a strong parliamentary opposition to the ministries in power. Because he was totally lacking in oratorical skills, his brilliant colleague Edmund Burke presented the group's case against Britain's efforts to suppress the American rebellion. During his brief second ministry Rockingham initiated peace negotiations with the American colonists and pushed through Parliament Burke's program for limiting the king's patronage power. In addition, his ministry obtained legislative independence for the Irish Parliament. Ross Hoffman's biography of Rockingham, The Marquis, was published in 1973.