Entering the House of Commons in 1790, Jenkinson soon became a leading Tory, serving as a member of the Board of Control for India (1793–96), master of the Royal Mint (1799–1801), foreign secretary (1801–04), home secretary (1804–06, 1807–09), and secretary for war and the colonies (1809–12). As foreign secretary he negotiated the short-lived Treaty of Amiens (signed March 27, 1802) with Napoleonic France.

After the assassination of Prime Minister Spencer Perceval (May 11, 1812), Liverpool reluctantly took his place, hoping to find and train a more brilliant successor. The War of 1812 with the United States and the final campaigns of the Napoleonic Wars were fought during his premiership. At the Congress of Vienna (1814–15), he strenuously urged the international abolition of the slave trade; within a few years the other European powers accepted this view.

In 1819 he strengthened the British monetary system by restoring the gold standard. Throughout his tenure he insisted that ecclesiastical and other appointments be justified by merit rather than by influence. Less enlightened was his attitude toward civil disturbances following industrial and agricultural failures: he suspended the Habeas Corpus Act for Great Britain in 1817 and for Ireland in 1822 and imposed other repressive measures in 1819. His position on proposals to repeal the Corn Laws (import duties on foreign foodstuffs) and to grant political rights to Roman Catholics was equivocal. After nearly 15 years in office, he was forced to retire because of a paralytic stroke.