Nicholas was born in Williamsburg, Virginia. He attended the College of William and Mary. According to Nicholas's entry in the Biographical Directory of the United States Congress, he served in the American Revolutionary War as commander of George Washington's Life Guard until the unit disbanded in 1783. This appears to be an error: his entry in American National Biography states that "he commanded Virginia volunteer units from the fall of 1780 until the following fall, but there is no evidence that he was actually involved in battlefield action.
During the deliberations, on June 6, 1788, Nicholas countered Patrick's Henry's objection that correcting defects in the new national Constitution by way of the Article V convention would be excessively difficult. Said Nicholas: "The conventions which shall be so called will have their deliberations confined to a few points; no local interest to divert their attention; nothing but the necessary alterations. They will have many advantages over the last Convention. No experiments to devise; the general and fundamental regulations being already laid down.
During the years 1794-1800, Nicholas served again in the State house of delegates. He was elected as a Democratic Republican to the United States Senate to fill the vacancy caused by the death of Henry Tazewell and served from December 5, 1799, until May 22, 1804, when he resigned to become collector of the port of Norfolk 1804-1807. He was elected to the U.S. House of Representatives in the Tenth and Eleventh Congresses and served from March 4, 1807, until his resignation November 27, 1809. Nicholas was chosen to be Governor of Virginia and served in that position 1814-1817.
Nicholas County, West Virginia was formed in 1843 and named in honor of Governor Nicholas.