Prime Minister, Compton became a Whig following an argument with his older brother, the Earl of Northampton. He was elected as Member of Parliament for Eye in 1698 and was appointed as Paymaster of Pensions in 1707. He retained the post, even when he left Parliament in 1710. In 1713 he was elected as the Member of Parliament for East Grinstead and in 1715 became Treasurer to the Prince of Wales before being elected Speaker of the House in 1715, where he served until 1727.

Compton was popular with the Prince of Wales, and Walpole sought to secure his position with the future George II by appointing Compton to his administration, as Paymaster of the Forces in 1722 and Lord Privy Seal in 1725. Compton was outmanoeuvred by Walpole on George II's accession and did not succeed in converting the monarch's patronage into high political office. In 1728, Walpole had Compton raised to the peerage as Baron Wilmington, to remove him from the Commons, and in 1730 he was created Earl of Wilmington. He threatened to resign during the Excise Crisis in 1733 but did not carry the threat through once he was offered the position as a Knight of the Garter. Upon Walpole's resignation from office, he became First Lord of the Treasury, but he died the following year.

During Compton's brief term in office the Mughal-Maratha Wars raged in India.