Prime Minister throughout much of the American War of Independence, North was first elected as Member of Parliament for Banbury in 1754 and joined the government as a junior Lord of the Treasury in 1759. He turned down positions under Lord Rockingham but was appointed Paymaster of the Forces in 1766 by Pitt and became a Privy Councillor. In 1767 he was appointed Chancellor of the Exchequer and in 1768 became Leader of the Commons as well.

North succeeded the Duke of Grafton as Prime Minister, keeping many previous ministers in their posts. In contrast to many of his predecessors he had a good relationship with George III. However, North's time in office was dominated by the American colonies, where his government's measures succeeded in inflaming the colonists, and the escalation of the conflict by 1780 to the British fighting a global war on four continents with no allies. North left office following a vote of no confidence in 1782. However, he returned to government as Home Secretary in coalition with the Whig leader Charles James Fox, who was detested by George III and who never forgave North for the perceived betrayal. The coalition succeeded in signing the Treaty of Paris, which formally ended of the American war, but lost power in December 1783. North never held high office again. He succeeded his father as Earl of Guildford in 1790.

In India, Warren Hastings became the first Governor General of Bengal during North's ministry, and the First Anglo-Maratha War, the Anglo-French War and the Second Anglo-Mysore War stretched British military resources. Opium was declared a Company monopoly, and in 1773 North's Regulating Act lent £1.4 million to the Company in return for reforms of its administrative practices.