Ordained in 1718, Butler became preacher at the Rolls Chapel in London, where he delivered his famous “Sermons on Human Nature” (1726), addressed to the practical side of Christian living. After several years as a parish priest, he was appointed in 1736 head chaplain to Caroline, wife of King George II. In the same year, he published his most celebrated work, The Analogy of Religion, Natural and Revealed, to the Constitution and Course of Nature, attacking Deist (Deism) writers whose approach to God consisted in arguing rationally from nature rather than from faith in the doctrine of revelation. Butler sought to demonstrate that nature and natural religion were encumbered with the same kind of uncertainties as revealed religion. The book, together with the Wesleyan revival, silenced the importance of Christian Deism in England. His Of the Nature of Virtue, appended to the Analogy, presented a refutation of hedonism and of the notion that self-interest is the ultimate principle of good conduct; for this work Butler has been considered by some critics to be one of the foremost British moral philosophers.

After the queen died in 1737, Butler went in 1738 to Bristol as bishop. His abilities as chaplain, however, had impressed the king, and in 1746 Butler was recalled to the royal household. A year later Butler declined an offer to become primate (archbishop of Canterbury), but in 1750 he accepted the bishopric of Durham. Among the many thinkers subsequently influenced by his arguments in favour of traditional theology was the Roman Catholic cardinal John Henry Newman (Newman, John Henry) (1801–90).