He entered Parliament in 1701 and briefly held the offices of Secretary of War and Treasurer of the Navy until he was dismissed with his Whig colleagues in 1710. The Tories impeached him for corruption in 1711 and expelled him from Parliament, making him a martyr for the Whig cause. On the accession of George I in 1714 he became Paymaster of the Forces and Chancellor of the Exchequer in 1715, but resigned in sympathy with his brother‐in‐law Townshend in 1717. The South Sea Bubble crisis brought Walpole to power in 1721 and he remained in office as leading minister (effectively the first Prime Minister) until 1742.

During his long period of power he strove for peace abroad and also did his best to avoid political controversy at home, especially on such contentious issues as religion; he strengthened the economy and by his mastery of the House of Commons and use of patronage he maintained political stability. He regularly presided over cabinet meetings and was thus generally regarded as the first effective Prime Minister; he insisted on cabinet loyalty and moved a long way towards the idea of the collective responsibility of the cabinet. In 1733 his unpopular attempts to impose excise duties on wine and tobacco were defeated in Parliament, but he placed a heavy duty on molasses imported into America, which became a major American grievance. He then faced an increasingly powerful opposition from within his own party in Parliament and lost an important patron when Queen Caroline died in 1737. After reluctantly going to war with Spain in 1739 and seeing Britain increasingly involved in the War of the Austrian Succession, he accepted a peerage and resigned in 1742.