Thomas Mann Randolph managed plantations at Varina and Edgehill and helped oversee Thomas Jefferson's Albemarle property during Jefferson's presidency. His agricultural work depended on enslaved labor. He experimented with contour plowing for hilly land, helped found the Agricultural Society of Albemarle, and published botanical observations. His 1790 marriage to Martha Jefferson linked household responsibilities with his political career.

Randolph served in Virginia's Senate in 1793–1794 and the United States House from 1803 to 1807. In Congress he worked on enrolled bills and legislation ending the transatlantic slave trade. During the War of 1812 he became colonel of the 20th United States Infantry and served on the northern frontier before resigning in 1814. Election to the House of Delegates in 1819 preceded three annual terms as governor from December 1819 to December 1822.

As governor, he supported the James River canal, public education, the University of Virginia and better penitentiary conditions. He also advocated gradual emancipation coupled with forced emigration of Black people. Returning to the legislature in 1823–1825, he worked on schools and prison administration. Debts, crop failures and unsuccessful financial decisions forced the sale of his estates and strained family relationships. A later appointment to survey the Georgia–Florida boundary ended without completion. He returned to Monticello, where he reconciled with his family before dying in 1828.