Educated at Queen's College, Oxford, Compton was ordained in 1666 and became bishop of Oxford in 1674 and of London in 1675. His Protestantism brought him into disfavour with the Roman Catholic James II, who in 1685 deprived him of his seat in the privy council. The next year, for refusing to suspend John Sharp, rector of St. Giles-in-the-Fields, whose antipapal sermons had offended the king, Compton was himself suspended. He gave his support to the seven bishops who made a petition against the king's Declaration of Indulgence (1687), and he was the only ecclesiastic to sign the invitation to William of Orange to come to England to overthrow James.

When John Tillotson was preferred to him as archbishop of Canterbury (1691), Compton suffered a bitter disappointment. Under Queen Anne, Compton gave full support to the Tories, and Francis Atterbury (Atterbury, Francis), bishop of Rochester, was his protégé. As bishop of London, Compton encouraged the newly founded Society for the Propagation of the Gospel and missionary work in America.