Greene County developed from the "Nolichucky settlement," established by pioneer Jacob Brown on land leased in the early 1770s from the Cherokee people.

Revolutionary War veteran, and state legislator, Col. Joseph Hardin made Greene County his home for a period of time, serving as justice of the peace and as one of the original trustees of Tusculum (then Greeneville) College.

As with yeomen farmers in much of East Tennessee, those in Greene County were generally Unionist and opposed to secession on the eve of the Civil War.

[5] Following the vote (the call for secession was passed statewide), the second session of the East Tennessee Convention convened in Greeneville.

A railroad bridge near Mosheim was among those destroyed by the East Tennessee bridge-burning conspiracy in November 1861.

Several of the conspirators who had taken part in the burning of this bridge were later captured and executed by Confederate supporters, including Jacob Hensie, Henry Fry, Jacob and Henry Harmon, and noted local potter Alex Haun.

[7] Most of Greene County is located within the Ridge-and-Valley Appalachians, a range characterized by long, narrow ridges alternating with similarly shaped valleys.

Bays Mountain, a prominent ridge in this range, forms much of Greene's northern border with Hawkins County.

[8] This range straddles Greene's border with North Carolina, and includes the county's two highest points: Gravel Knob, which rises to over 4,840 feet (1,480 m), and 4,844-foot (1,476 m) Camp Creek Bald (it's uncertain which is higher due to lack of an exact measurement for Gravel Knob's elevation).

This river is impounded by Nolichucky Dam south of Greeneville, creating Davy Crockett Lake.