While Depew was active in the Vanderbilt roads in New York he held concurrent positions with many other railroads and companies. He was president of West Shore Railroad. He served on the boards of directors for the New York and Harlem Railroad, the Chicago and North Western Railway, the Chicago, St. Paul, Minneapolis and Omaha Railroad, the Cleveland, Cincinnati, Chicago and St. Louis Railroad, the Delaware and Hudson Railroad, the New Jersey Junction Railroad, the St. Lawrence and Adirondack Railroad, the Walkill Valley Railroad, the Canada Southern Railroad.
Aside from railroads, Depew also served on the boards of director for Western Union, the Hudson River Bridge Company, the Niagara River Bridge Company, the New York State Realty & Terminal Company, the Union Trust Company, Equitable Life Assurance Company, and Kensico Cemetery Association. He was appointed regent of the University of the State of New York in 1877 and served until 1904.
He was a member of the New York State Assembly in 1862 and 1863, in the latter year its Acting Speaker while Speaker Theophilus C. Callicot was under investigation. From 1863 to 1865 he was New York Secretary of State. He was one of the commissioners appointed to build the state capitol 1874; in 1867 appointed clerk of Westchester County by Governor Fuller, but resigned after a short service; made immigration commissioner by New York Legislature in 1870, but declined to serve; member of boundary commission of the state of New York in 1875; had also been commissioner of quarantine and president of Court of Claims of New York City and commissioner of taxes and assessments for the city and county of New York; defeated for Lieutenant Governor of New York on the Liberal Republican-Democratic ticket in 1872; candidate for United States senator in 1881, but withdrew after the fortieth ballot, declined nomination as a senator in 1885, but elected to the Senate in 1898 and served from March 4, 1899, to March 3, 1911; stumped the state of New York for John C. Fremont in 1856 and for Lincoln in 1860; delegate-at-large to Republican National conventions 1888-1904 and delegate to all following conventions, including 1928, being elected the day before he died; made the nomination speeches for Harrison in 1892, Governor Morton in 1896, and Fairbanks in 1904; at the convention in 1888 received ninety-nine votes for the presidential nomination, and in 1892 declined an appointment as Secretary of State in Harrison's cabinet; Adjutant of the 18th Regiment, New York National Guard, which served in the American Civil War, and later Colonel and Judge Advocate of the 5th Division, on the staff of Major General James W. Husted of the New York Guard, trustee of Peekskill Military Academy; president of New York State Society of the Sons of the American Revolution, of The Pilgrims from 1918 until his death, of the St. Nicholas Society, and of the Union League for seven years (member since 1868 and elected honorary life member at the close of his presidency); an officer of the French Legion of Honor; vice president of New York Chamber of Commerce 1904-08 (member since 1885).
Death due to bronchial pneumonia. Buried in family mausoleum in Hillside Cemetery, Peekskill.
His father, Isaac Depew, was a merchant and farmer; pioneer in river transportation between Peekskill and New York; son of Abraham Depew, who served in the Revolutionary Army, and Catherine (Crankheit) Depew, great-grandson of Captain James Cronkite of the Continental Army; descendant of Frangois DuPuy, a French Huguenot, who came to America about 1661, settled first in Brooklyn, N. Y., and in 1685 bought land from the Indians at the present site of Peekskill. Mother, Martha Minot (Mitchell) Depew; daughter of Chauncey Root Mitchell, a lawyer, and Ann (Johnstone) Mitchell; granddaughter of the Rev. Justus Mitchell (BA 1776); great-granddaughter of the Rev. Josiah Sherman (B A. Princeton 1754, honorary M.A. Yale 1765), who served as a Chaplain with rank of Captain in the Revolutionary War and the brother of American founding father Roger Sherman; descendant of Matthew Mitchell, who came to Boston from England in 1635, descended also from Capt. John Sherman, an English officer, who was born in Dedham, Essex County, in 1615, and from the Rev. Charles Chauncey (B.A. Trinity College, Cambridge, 1613), who came to Plymouth in 1637 and was the second president of Harvard.
Married (1) November 9, 1871, in New York City, Elise A., daughter of William and Eliza Jane (Nevin) Hegeman. One son, Chauncey Mitchell, Jr. . Mrs. Depew died May 7, 1893 Married (2) December 27, 1901, in Nice, France, May, daughter of Henry and Alice (Hermann) Palmer.
Depew was also the paternal uncle of Ganson and Chancey Depew, sons of his brother William Beverly Depew. Ganson Depew was a vice president of the Buffalo & Susquehanna Coal Company; and the personal assistant of his father-in-law Frank Henry "F.H." Goodyear. Goodyear was the president of the Buffalo & Susquehanna Railway. Chancey DePew, like his uncle, also worked for the Vanderbilt Railway Systems.