He was the second son of Sir Stephen Fox, and inherited a large share of his father's wealth. He squandered it soon after attaining his majority, and went to the Continent to escape from his creditors. There he made the acquaintance of a woman of fortune, who became his patroness and was so generous to him that, after several years’ absence, he was in a position to return home and, in 1735, to enter parliament as member for Hindon in Wiltshire. He became the favourite pupil and devoted supporter of Sir Robert Walpole, achieving unequalled and unenviable proficiency in the worst political arts of his master and model. A skilled speaker, he was able to hold his own against Pitt himself. This helped him progress in the House of Commons, becoming an indispensable member of several administrations. He was surveyor-general of works from 1737 to 1742, was member for Windsor from 1741 to 1761; lord of the treasury in 1743, Secretary at War and member of the Privy Council in 1746, and in 1755 became leader of the House of Commons, Secretary of State for the Southern Department and a member of the cabinet under the Duke of Newcastle. In 1757, in the rearrangements of the government, Fox was ultimately excluded from the cabinet, and given the post of Paymaster of the Forces. During the war, Fox devoted himself mainly to accumulating a vast fortune. In 1762 he again accepted the leadership of the House, with a seat in the cabinet, under the Earl of Bute, and managed to induce the House of Commons to approve of the Treaty of Paris (1763); as a reward, he was raised to the House of Lords with the title of Baron Holland of Foxley, Wiltshire, on 16 April 1763.
Lord Holland eloped with and married the much younger Lady Caroline Lennox, daughter of the Duke of Richmond, in 1762. She was created Baroness Holland, of Holland, Lincolnshire. The noted Whig politicians Charles James Fox and Henry Richard Vassall-Fox, 3rd Lord Holland were his son and grandson, respectively.
In 1765 Fox was forced to resign the paymaster generalship, and four years later a petition of the livery of the City of London against the ministers referred to him as "the public defaulter of unaccounted millions." The proceedings brought against him in the court of exchequer were delayed by a royal warrant; and he proved that in the delays in making up the accounts of his office he had not broken the law. From the interest on the outstanding balances he had nonetheless amassed a fortune. He tried in vain to obtain promotion to an earldom, a title on which he had set his heart, and he died at Holland House, Kensington, a sorely disappointed man, with a reputation for cunning and unscrupulousness, the most unpopular politician of his day.