Tompkins was the second vice President to serve two full terms, after John Adams, who was George Washington's vice President from 1789 to 1797. He would be the last to do so for nearly a century, until Thomas R. Marshall, who served under Woodrow Wilson from 1913 to 1921. (Since Marshall, John Nance Garner, Richard M. Nixon, George H. W. Bush, Al Gore, Dick Cheney, and Joe Biden, have done so as well. Apart from Garner, they all left the vice presidency at the same time as the President they had served under.)

On February 20, 1798, Daniel Tompkins married 16-year-old Hannah Minthorne, the daughter of Mangle Minthorne, an Assistant Alderman of New York City. The couple had eight children, including Arietta Minthorn Tompkins (born July 31, 1800), who married a son of Smith Thompson in 1818, and (Mangle) Minthorne Tompkins (December 26, 1807 – June 5, 1881), who was the Free Soil Party candidate for Governor of New York in 1852. Their children Hannah and Minthorne were named after their mother, and Hannah and Minthorne streets in Staten Island are named for them. Hannah was ill in the year before her husband became vice President, and did not attend his inauguration. She survived him by nearly four years in Tompkinsville, Staten Island.

Born in Scarsdale, New York, Tompkins practiced law in New York City after graduating from Columbia College. He was a delegate to the 1801 New York constitutional convention and served on the New York Supreme Court from 1804 to 1807. In 1807, he defeated incumbent Morgan Lewis to become the Governor of New York. He held that office from 1807 to 1817, serving for the duration of the War of 1812. During the war, he often spent his own money to equip and pay the militia when the legislature wasn't in session, or would not approve the necessary funds.

On April 30, 1807, he defeated the incumbent Governor Morgan Lewis – Tompkins received 35,074 votes, Lewis 30,989 – and remained in office as Governor of New York until 1817. He was reelected in 1810, defeating Jonas Platt – Tompkins 43,094 votes, Jonas Platt 36,484. In 1813 he defeated Stephen Van Rensselaer – Tompkins 43,324 votes, Van Rensselaer 39,718 – and in 1816, he beat Rufus King – Tompkins 45,412 votes, King 38,647. Tompkins was supported by DeWitt Clinton in his first run for office, but Tompkins later broke with Clinton by supporting James Madison over Clinton in the 1808 presidential election.

Four forts in New York State in the War of 1812 were named for Governor Tompkins, in Staten Island, Sackets Harbor, Buffalo, and Plattsburgh.

Tompkins entered in office in poor health, the result of a fall from a horse on November 3, 1814. Tompkins's finances were also quite poor, as Tompkins had borrowed money to Finance the war effort during the War of 1812, and Tompkins slipped into alcoholism. Tompkins had failed to adequately document his expenses, and both the New York legislature and the federal government refused to fully reimburse him. With poor physical and financial health, Tompkins spent much of his vice presidency outside of Washington, D.C., and Tompkins made for a poor presiding officer of the Senate while it debated the Missouri Compromise in 1820. In 1823, Tompkins finally won compensation from the federal government, but he continued to drink heavily and was unable to resolve his Business affairs.

In 1815 Tompkins established a settlement along the eastern shore of Staten Island that came to be called Tompkinsville. He built a dock along the waterfront in the neighborhood in 1817 and began offering daily steam ferry Service between Staten Island and Manhattan. In 1816 he purchased much of the land later known as Tompkinsville from the Church of St. Andrew, but his financial troubles later led the church to foreclose. His son-in-law and daughter, Dr. John S. and Hannah Westervelt then bought the property, which they later divided into many lots to sell off.

Tompkins was the Democratic-Republican Party's vice presidential nominee in the 1816 presidential election. The ticket of James Monroe and Tompkins easily prevailed over limited Federalist opposition. He served as vice President from 1817 to 1825, and was the only 19th century vice President to serve two full terms. In 1820, he sought another term as Governor of New York, but was defeated by DeWitt Clinton. After the War of 1812, Tompkins was in poor physical and financial health, the latter condition stemming largely from his spending for the military effort during the War of 1812. He fell into alcoholism and was unable to re-establish fiscal solvency despite winning partial reimbursement from the federal government in 1823. He died in June 1825, soon after leaving office.

Many New York Democratic-Republicans supported Tompkins for President in the 1816 presidential election, but James Monroe received the party's nomination. Tompkins was instead elected as Monroe's running mate, and Tompkins won reelection in 1820, serving from March 4, 1817, to March 4, 1825. In 1820, while serving as vice President, he ran for Governor of New York against incumbent DeWitt Clinton. The election was held in April 1820; Tompkins lost. He received 45,900 votes while Clinton received 47,447. In 1821, he was a delegate to the New York State Constitutional Convention, serving as its President.

Tompkinsville, a neighborhood on Staten Island, is named for Tompkins. There is also a Masonic lodge in the town named for him. Tompkins is credited with being one of the founding members of the Brighton Heights Reformed Church on Staten Island. The church was founded in 1823, during his term as vice President. Its first meeting place was in what was known as Quarantine, a predecessor of the facility on Ellis Island.

He died in Tompkinsville on June 11, 1825, 99 days after leaving office, and was interred in the Minthorne vault in the west yard of St. Mark's Church in-the-Bowery, New York City, as was his wife. His post-vice presidency lifespan is the shortest of any vice President, and he also lived the shortest life of any Vice President. He was the youngest person to become Vice President until John C. Breckinridge, and the only 19th century vice President to serve two full terms under the same President.

In 1817, Governor Tompkins suggested that July 4, 1827, be set as the date on which all slaves in New York state—including those who were born before the Gradual Manumission Act of July 4, 1799, (and who were therefore not eligible for freedom)—should be freed.

Tompkins was mentioned by Kris Kringle in the 1947 film Miracle on 34th Street. The screenplay was incorrect, however, in that Kringle mentions that Tompkins served as vice President under John Quincy Adams when Adams' vice President was actually John C. Calhoun. (Tompkins was the 6th vice President and Quincy Adams was the 6th President, leading to confusion in the script).

Tompkins was Grand Master of the Grand Lodge of New York in 1820 and 1821. The Daniel D Tompkins Memorial Chapel at the Masonic Home in Utica, New York was built in his honor in 1911. The Grand Lodge of New York celebrated the Centennial of the chapel on June 25, 2011.