Born in Little Britain, New York, the son of James Clinton, he was educated at what is now Columbia University. He became the secretary to his uncle, George Clinton, who was the governor of New York. Soon after he became a member of the Anti-Federalist Party. DeWitt Clinton was a member of the New York state legislature from 1797 until 1802. He then stepped up to becoming a member of the United States Senate. Unhappy with living conditions in newly built Washington, DC he resigned his Senate seat in 1803, to become the Mayor of New York City. He served as Mayor in 1803-07, 1808-10 and 1811-15.

In 1812 Clinton ran for President of the United States as candidate of the Federalists and anti-war Republicans, but was defeated by James Madison.

Clinton was able to accomplish many things as a leader in civic and state affairs such as improving the New York public school system, encouraging steam navigation and modifying the laws governing criminals and debtors.

In 1817 DeWitt Clinton became the governor of New York until 1823. While governor he was largely responsible for the creation of the Erie Canal. He imagined a Canal from Buffalo, New York on the Eastern Shore of Lake Erie to Albany, New York on the upper Hudson River, a distance of almost 400 miles. So, in 1817 he persuaded the state lawmakers to provide 7 million dollars for the construction of a Canal 363 miles long and 40 feet wide, and four feet deep.

In 1825, when the Erie Canal was finished, Governor DeWitt Clinton opened it, sailing in the packet boat Seneca Chief along the Canal into Buffalo. After sailing from the mouth of Lake Erie to New York City, he emptied two casks of water from Lake Erie into New York Harbor, celebrating the first connection of waters from East to West in the ceremonial "Wedding of the Waters".

Although railroads did compete with the Erie Canal, the advent of railroads did not cause the canal to become defunct. As late as 1852, the canal carried thirteen times more freight tonnage than all the railroads in New York state, combined; it continued to compete well with the railroads through 1882, when tolls were abolished.

The Erie Canal played a big role in New York and made boomtowns out of Buffalo, Rochester, Syracuse, Rome, Utica and Schenectady and made an immense contribution to the wealth and importance of New York City and New York State. Nevertheless, its impact went much further - as it increased trade throughout the nation by opening eastern markets to Midwest farm products and encouraged western immigration.

Clinton died at the age of 59 and was interred in the Green-Wood Cemetery in Brooklyn, New York.