Wythe County was organized by an Act of the Virginia Assembly on December 1, 1789, and was named for George Wythe, a noted lawyer of Eastern Virginia, one of the signers of the Declaration of Independence and the designer of the Virginia Seal.

The first county court session was held at the home of James McGavock at Fort Chiswell on May 25 the following year, where the Montgomery County Court had been meeting for several years. On that date the court accepted the offer of Christopher Simmerman who donated ninety acres for the town, and the offer of John Davis who contributed the remaining ten acres with a large spring.

When Wythe County was formed the area included part of what is now the eastern part of Smyth County, the western part of what is now Pulaski County, all of Grayson and Carroll counties, and most of what is now Bland County. By 1861 the county limits had been permanently established.