Entering politics as a Republican, Depew served as a member of the New York Assembly (1861–62) and as secretary of state of New York (1864–65). In 1866 he declined an appointment as the first U.S. minister to Japan in order to become an attorney and lobbyist for Cornelius Vanderbilt's New York and Harlem Railroad. Eventually he rose to be president of the New York Central and Hudson River Railroad (1885–98) and board chairman of the entire Vanderbilt railway system (from 1898). A candidate for the Republican nomination for president in 1888, he withdrew in favour of Benjamin Harrison, whose successful campaign he strongly supported. In 1892 he declined Harrison's offer of the secretaryship of state. He later served two terms (1899–1911) as a U.S. senator from New York.