Manning was the son of a banker and member of Parliament. He was associated with the Oxford movement, was ordained priest in the Church of England (1833), and became archdeacon of Chichester (1840). Manning's attraction to Roman Catholicism was based on his opposition to government interference in ecclesiastical affairs. He was disturbed when the Privy Council overruled the refusal of a bishop to institute an Anglican divine, George C. Gorham, on grounds of unorthodoxy (1850). Manning was received into the Roman Catholic Church on April 6, 1851, and ordained priest (his wife had died in 1837) by Cardinal Nicholas Wiseman on June 15, 1851. He then studied theology at Rome. In 1857 he founded the Oblates of St. Charles. His rapid rise in the church culminated in his appointment as archbishop of Westminster (the Roman Catholic primatial see of England) in 1865 and his elevation to the rank of cardinal in 1875.

As archbishop Manning was a vigorous builder of Catholic schools and other institutions. An extreme Ultramontanist, he accused John Henry (later Cardinal) Newman of minimizing the authority of Rome, and in the debates on papal infallibility at the First Vatican Council he advocated a less cautious definition than that eventually adopted. Manning won general public regard for his social concern and his successful intervention in the 1889 London dock strike.