Dandridge, the county seat, was organized in 1793. It has long been promoted as the second-oldest established town in Tennessee. Dandridge was named for Martha Dandridge Washington, the wife of the first president. This is the only town in the nation named to honor her. Dandridge was an attractive location for early settlers because of the fertile land, bountiful game, and the plentiful supply of fresh water. In 1792 there was sufficient settlement for William Blount, Governor of the Territory South of the Ohio River, to carve out a new county named Jefferson in honor of the Secretary of State, Thomas Jefferson. Frances Dean supplied 50 acres of land for the new county seat of Dandridge. The current courthouse (Greek Revival architecture) was completed in 1845. The town grew and thrived until approximately 1858 when the East Tennessee and Virginia Railroad completed a line from Knoxville to Virginia which passed through New Market and Mossy Creek. The transportation system shifted the growth away from Dandridge but the town remained prominent due to the location of the county seat.

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East Tennessee has always been different from the rest of the state. During the Civil War, East Tennessee was predominantly pro-Union. In June, 1861, a Union convention was held in Greeneville, Tennessee. The delegates petitioned the legislature to form a new state out of East Tennessee and those Middle Tennessee counties that did not wish to secede. When the petition was denied, East Tennesseans began joining the Union Army. Jefferson County was especially affected by this division of loyalties to the Union.

Jefferson County suffered during the War. A number of antebellum houses and buildings survived because of the county‘s pro-Union stand.