According to the U.S. Census Bureau, the county has a total area of 302 square miles (780 km
2), of which 281 square miles (730 km2) is land and 22 square miles (57 km2) (7.2%) is water. Grainger County is bounded on the northwest by the Clinch River (impounded by Norris Dam to form Norris Lake) and on the southeast by the Holston River (including Cherokee Lake). Clinch Mountain is a major geographic feature that effectively separates the county into a southern section (including Rutledge) and a northern section (including Washburn).

Grainger County was formed from Knox and Hawkins Counties in 1796, the year Tennessee became a state. It is named for Mary Grainger Blount, wife of William Blount. Anderson, Claiborne, Campbell, Hamblen, Hancock, Scott and Union Counties were formed from parts of the original Grainger County.

Like many East Tennessee counties, Grainger County was generally opposed to secession from the Union. In Tennessee’s Ordinance of Secession referendum on June 8, 1861, Grainger County voters rejected secession by 1,756 to 495.