Nicholson was born near Franklin, Tennessee in Williamson County. He attended the University of North Carolina at Chapel Hill, graduating in 1827. He studied law and was admitted to the bar in 1831, opening a law practice in Columbia, Tennessee. He edited the Western Mercury, a paper then published in Columbia, from 1832 to 1835. He also served in the Tennessee House of Representatives from 1833 to 1839. In 1840 the Tennessee General Assembly elected him, on an interim basis, to succeed to the U.S. Senate seat vacated by the death of Senator Felix Grundy. He served in that office from December 25, 1840 to February 7, 1842. From 1843 to 1845 he served in the Tennessee State Senate, moving to Nashville during this period, and edited the Nashville Union from 1844 to 1846. From 1846 to 1847 he served as a director, and then as president, of the Bank of Tennessee.

In 1853 President Franklin Pierce wished to appoint him to the Cabinet, but he declined to serve. He edited the Washington Union from 1853 to 1856 and subsequently served as public printer to the United States House of Representatives.

In 1858 Nicholson was again elected to the United States Senate from Tennessee by the Tennessee General Assembly. He served from March 4, 1859 to March 3, 1861, when he withdrew from participation in the Senate in anticipation of Tennessee secession from the Union, which occurred the next month. Later in 1861, he was formally expelled from the Senate, as were all Senators from the states joining the Confederacy with the sole exception of his fellow Tennessean Andrew Johnson, a loyal Unionist. After the war, Nicholson served as Chief Justice of the Tennessee Supreme Court from 1870 until his death. He was buried in Columbia's Rose Hill Cemetery.

This article incorporates facts obtained from the public domain Biographical Directory of the United States Congress.