Entering Parliament as a Whig in 1820, Derby held office under Viscount Goderich (1827–28) and became chief secretary for Ireland under Lord Grey in 1830, joining the Cabinet in 1831. In 1834 he resigned over the Irish Church question, but he served under Sir Robert Peel (Peel, Sir Robert, 2nd Baronet) (1841) only to resign again (1845) over the repeal of the Corn Laws (Corn Law). He succeeded to the earldom in 1851 and was premier in 1852, 1858, and 1866; among his legislation were the removal of Jewish discrimination in Parliament membership, the transfer of India's administration from the East India Company to the crown, and the Reform Bill of 1867.

Derby disliked the drudgery of office and as Conservative leader seemed weak and indolent beside Benjamin Disraeli (Disraeli, Benjamin, Earl Of Beaconsfield, Viscount Hughenden Of Hughenden), who nonetheless admitted, “He abolished slavery, he educated Ireland, he reformed parliament.” Derby is chiefly remembered as epitomizing the aristocratic amateur; he excelled in whatever he did: as a racehorse owner, as a benevolent if autocratic landowner, and as a scholar who won the chancellor's Latin verse prize at Oxford and published a blank verse translation of the Iliad (1864). He nurtured the Conservatives and helped the protectionists survive difficult years while he educated them to accept Disraeli as his successor and to prepare for electoral victory. Though a somewhat neglected figure, Derby was a founder of modern Conservatism in Britain and a key figure linking the old and the new ruling classes.