George Wythe Randolph was born to Thomas Mann Randolph, Jr. (01 October 1768-20 June 1828) (U.S. Congressman and Governor of Virginia) and Martha "Patsy" Jefferson (27 September 1772-10 October 1836), daughter of U.S. President Thomas Jefferson (13 April 1743-04 July 1826), at his grandfather's home, "Monticello", in Charlottesville, Albemarle County, Virginia on 10 March 1818.

     As a young man, he was briefly schooled in Cambridge, Hampshire County, Massachusetts and served from age 13 to 19 as a midshipman in the U.S. Navy before attending University of Virginia in Charlottesville, Albemarle County, Virginia. He then settled in Richmond, became a lawyer, and married Mary Elizabeth Adams (1830-1871) on 10 April 1852. In 1860, he organized the "legendary" Richmond Howitzers, a state militia artillery unit that is renowned for its service during the war. He was a delegate to the Virginia Secession Convention the following spring, and voted in favor of withdrawal from the Union.

     When the war came, he was commissioned a major in the Confederate Army. In the Battle of Big Bethel (10 June 1861), one of the very first fights of the war, he was Chief of Artillery under Col. (later Brig. Gen. and Maj. Gen.) John Bankhead Magruder (01 May 1807-18 February 1871). For his actions, Randolph was promoted to Brigadier General on 12 February 1862.

     He was appointed Secretary of War by President Jefferson Davis (03 June 1808-06 December 1889) on 18 March 1862, and took office on 24 March 1862. He was effective with coordinating the work of the field commanders, but Davis resented a decision he made without presidential approval. Bitter over the affair, Randolph resigned on 17 November 1862.

     Discovering he had tuberculosis, he traveled abroad in hopes that his health might improve. Unfortunately for him, it did not. Following the war, he returned to Virginia and died at "Edgehill", near "Monticello", on 03 April 1867. Randolph is buried, with many of his famous family members, in the "Monticello" Graveyard in Charlottesville, Albemarle County, Virginia.