Ashe County was inhabited by Native Americans, which included the Cherokee, Creek, and Shawnee tribes. Pieces of broken pottery, arrowheads, and other Native American artifacts have been found, indicating their presence. Most of these artifacts have been found in the Old Fields area of Ashe County.
 
The earliest Europeans to explore Ashe County were Bishop Augustus Gottlieb Spangenberg – head of the Moravian Church in America – and his associates, Timothy Horsefield, Joseph Mueller, Henry Antes, Johan Merck, and Herman Loesch. Bishop Spangenberg wrote about his journey in Ashe in a diary that has been preserved by the Moravian church.
 
He was given 100,000 acres in Virginia as a place for his fellow Moravians to settle. The only one of Spangenberg's group to return and permanently settle in Ashe County was Herman Loesch.
 
Other early settlers were David Helton, William Walling, William McLain and Daniel Boone, the famous pioneer. With the exception of Boone, these men and their families all settled in Ashe in 1771.
 
During the Revolutionary War one skirmish was fought in Ashe County. It is called the "Battle of the Big Glades". The battle was fought in July 1780 between a force of Americans, led by Captain Robert Love, and a force of 150 British Loyalists on their way to Charlotte to join Lord Cornwallis, the British commander in the Southern colonies. The Americans won the skirmish.
 
In the 1780s, Ashe County was considered a part of the "State of Franklin". It consisted of three counties – Washington, Greene, and Sullivan. Ashe was considered to be a part of Washington County. The "State of Franklin" marked the beginnings of the State of Tennessee.
 
Ashe County did not formally become a part of North Carolina until 1785. In late 1799 composed of 977 square miles, Ashe was finally pronounced an official county of the United States and of North Carolina.
 
Many family surnames noted in the 1800 Ashe County Census, Blevins, Hart, Bare, Barker, Stamper, Miller, Burkett, Gambill, Baldwin, and Ballou as a sample, are still present today. Ashe County was named in honor of Samuel Ashe, a Revolutionary patriot, a superior court judge, and the Governor of North Carolina from 1795 to 1798.
 
From 1807 to 1913, the county went through numerous boundary changes. In 1849, to form Watauga County, the southwestern part of Ashe County was combined with parts of Caldwell County, Wilkes County, and Yancey County. Ten years later in 1859, the eastern part of the remainder of Ashe County became Alleghany County.