William Windom was born in 1827 in Belmont County, Ohio. He was first schooled at home and in small common schools but ultimately entered the Martinsburg Academy in Ohio, where he studied law under Judge R. C. Hurd. Windom was admitted to the Ohio bar in 1850. In 1851, he became partners with his former law teacher. When Hurd became judge of the court of common pleas in 1852, Windom partnered with Daniel Norton in a relationship that lasted for several years. That same year, Windom was elected as prosecuting attorney for Knox County.

Deciding not to run for reelection in 1854, Windom called for a Republican Party convention in Mount Vernon, where he launched an unsuccessful bid to become Ohio's attorney general. Following this disappointment, Windom and Norton moved their law practice to Minnesota, where in 1859, Windom was elected to the United States House of Representatives. Windom served in the House for ten years, trying unsuccessfully in 1865 to run for the U.S. Senate. In 1870, he assumed a vacant U.S. Senate seat for one year before being elected to the Senate in his own right in 1871; he was reelected again in 1877. In 1881, President James Garfield appointed Windom secretary of the treasury, a post Windom resigned in November of that year following Garfield's assassination.

Windom then picked up where he left off, reassuming the Senate seat he had vacated to join Garfield's cabinet. He served out his term, failed to secure reelection in 1882, and moved to New York City, where he practiced law until 1889. That year, William Windom reprised his role as secretary of the treasury, this time in President Benjamin Harrison's administration. Again, he did not hold his post as secretary of the treasury for long, for he died in office in 1891.