In 1786 James White built a fort on the southernmost edge of frontier settlement in present-day East Tennessee. William Blount, governor of the Territory of the United States South of the River Ohio (also called the Southwest Territory), selected the site of White's fort as the capital in 1791 and gave it the name Knoxville in honor of Revolutionary War hero General Henry Knox. Governor Blount created Knox County, also named for Henry Knox, from parts of Greene and Hawkins Counties on June 11, 1792. Knoxville has served as the county seat from the county's creation. Knox County currently contains 509 square miles. The Tennessee River originates near the center of the county from the union of the Holston and French Broad Rivers.

Governor Blount designated Knoxville as the capital of the Southwest Territory from 1791 to 1796. Knoxville also served as the capital of the State of Tennessee from 1796 to 1812 and briefly in 1817-18. General John Sevier, a resident of Knox County, served as governor of Tennessee (1796-1801, 1803-1809). No state capitol building was constructed until 1845 on the present building in Nashville, so the general assembly met in taverns and public buildings. Blount Mansion, the home of Governor Blount, is the only National Historic Landmark in the county.