Sickles attended the University of the City of New York, later studied law, and in 1846 was admitted to the bar. He immediately became active in the Democratic Party, and in 1847 he launched his long political career by winning a seat in the state legislature.

In 1853 Sickles—then corporation counsel for the city of New York—acquired the land for Central Park. He resigned his post the same year to become secretary to the U.S. legation in London. Back in the United States in 1855, Sickles won consecutive terms in the New York state senate in 1856 and 1857 and then entered national politics, serving from 1857 to 1861 as a Democrat in the U.S. House of Representatives.

On Feb. 27, 1859, Sickles shot and killed Philip Barton Key, who was the son of Francis Scott Key. Sickles claimed temporary insanity (the first time that defense was used in the United States) arising from what he believed were Key's amorous intentions toward his wife. Sickles was acquitted.

Sickles fought in the Civil War, rising from colonel to major general. From 1865 to 1867 he was military governor of North and South Carolina, but his performance displeased President Andrew Johnson, and he was relieved in 1867. Two years later he retired from the Army. From 1869 to 1873 he served as U.S. minister to Spain. In 1893–95 Sickles served a final term in the U.S. House of Representatives, then retired from national politics after defeat in his try for reelection in 1896.