Entering the House of Commons in 1782, Grenville became its speaker in January 1789, home secretary in June of that year, and president of the Board of Control in March 1790. Created Baron Grenville on Nov. 25, 1790, he then became leader of the House of Lords. From June 8, 1791, to Feb. 10, 1801, he served under his cousin William Pitt (Pitt, William, The Younger) the Younger as secretary of state for foreign affairs. To crush English radicalism encouraged by the French Revolution, Grenville introduced the Habeas Corpus Suspension Act (1794) and other measures. He and Pitt resigned (1801) when King George III refused to consider granting political rights to Roman Catholics.

When Pitt resumed the premiership in May 1804, Grenville declined to join the government because his greatest political ally, Charles James Fox, was excluded from office at the king's insistence. After Pitt's death (Jan. 23, 1806) Grenville formed a coalition of the former prime minister Henry Addington's followers, Foxites, and his own friends. His government failed to make peace with Napoleonic France and otherwise accomplished little apart from outlawing the slave trade in 1807. Its advocacy of a Catholic Relief Bill caused George III to dismiss Grenville in March 1807 after the latter refused to pledge himself never again to trouble the king on the subject. Grenville's refusal kept him out of office in 1809 and again in 1812. Until 1817, when he supported the government's measures to suppress radicalism, he generally voted with the Whigs in opposition. A paralytic stroke ended his active political career in 1823. Grenville was chancellor of Oxford University from 1810 to 1834. He died without male issue, and his title became extinct.