In 1791, Burr was elected to the United States Senate, where he served until 1797. He later ran as the Democratic-Republicanpresidential candidate in the 1800 election. An electoral college tie between Burr and Thomas Jefferson resulted in the House of Representatives voting in Jefferson's favor, with Burr becoming Jefferson's vice president due to receiving the second-highest share of the votes. Although Burr maintained that he supported Jefferson, the president was somewhat at odds with Burr, who was relegated to the sidelines of the administration during his vice presidency and was not selected as Jefferson's running mate in 1804 after the ratification of the 12th Amendment to the U.S. Constitution.

During his last year as vice president, Burr engaged in the duel in which he fatally shot Alexander Hamilton, the former Secretary of the Treasury and his political rival, near where Hamilton's son Philip Hamilton had died in a duel three years prior. Although dueling was illegal, Burr was never tried and all charges against him were eventually dropped. Nevertheless, his killing of Hamilton ended Burr's political career.

Burr traveled west to the American frontier, seeking new economic and political opportunities. His secretive activities led to his 1807 arrest in Alabama on charges of treason. He was brought to trial more than once for what became known as the Burr conspiracy, an alleged plot to create an independent country led by Burr, but was acquitted each time. For a short period of time Burr left the United States to live as an expatriate in Europe. He returned in 1812 and resumed practicing law in New York City. Burr died on September 14, 1836, at the age of eighty.