Prime Minister, Pelham-Holles became one of the greatest landowners in Great Britain when he came of age in 1714, inheriting from both his father and uncle. He was influential in the Whigs, and organised to ensure the public acceptance of the Hanoverian monarchs on the death of Queen Anne. George I rewarded his services with the title of Earl of Clare in 1714 and Duke of Newcastle in 1715.

Pelham-Holles first took political office as Lord Chamberlain in 1717. In 1724 he was appointed Secretary of State for the Southern Department but deferred in matters of foreign policy to Lord Townshend until he was forced from office. During the 1730s, Pelham-Holles and his brother Henry Pelham became Robert Walpole's most influential political colleagues.

Thomas had generally followed Walpole's policy of seeking to avoid military conflict but began to cultivate a reputation as a patriot at the outbreak of the War of Jenkins' Ear. He continued to control foreign policy when his brother succeeded Walpole as Prime Minister, but on Hnery's death he himself became Prime Minister in 1754, serving two separate terms. He continued to dominate foreign policy and in his second term developed a surprising partnership with William Pitt, previously one of his main critics. In 1762, George III appointed Lord Bute in place of Pelham-Holles and Pitt, who he did not trust. Pelham-Holles made a final brief return to office as Lord Privy Seal in 1765, but spent the remaining years until his death in opposition.

During Pelham-Holles's second term as Prime Minister, large swathes of Bengal were seized by the Company and the French were almost entirely ousted from India.