Oconee County was named after a historic Cherokee town and the word "Ae-quo-nee", meaning "land beside the water."

The town was located along the Cherokee trading path of the early 18th century between the English colonial Atlantic port of Charleston and the Mississippi River to the west.

Oconee Town did not develop around an ancient platform mound like those built by ancestral peoples during the period of the Southern Appalachian Mississippian culture, approximately 1000CE to 1500CE.

Through the centuries of their long occupancy, the Cherokee would replace the council house, and maintain and add to nearby mounds, building in distinctly colored layers of earth that are visible to archeologists.

[4][5] Due to its geographic position, the town was at the intersection of the trading path and the Cherokee treaty boundary of 1777.

In 1792, the newly formed South Carolina State Militia built a frontier outpost near the town site, and named it Oconee Station.

European-American settlement in this far western area of the colony did not begin until the late eighteenth century.

[8] Three large man-made lakes provide residents with sport fishing, water skiing, and sailing as well as hydroelectric power.

Lake Jocassee is the third-largest and is a source of hydroelectric energy, but is also popular for its scenery and numerous waterfalls.

Bad Creek Reservoir, located in the mountains above Jocassee, is also used for generating electricity during peak hours.

Because of the dramatic changes in water level due to these uses, boating and swimming are prohibited in this reservoir.

[25] As of April 2024[update], some of the largest employers in the county include Apex Tool Group, BorgWarner, CSL Plasma, Duke Energy, Ingles, Itron, Kelly Services, Prisma Health, Sandvik, Schneider Electric, and Walmart.

[26] The Oconee region is mentioned in the song "Yankee Bayonet (I Will Be Home Then)" by the indie rock group the Decemberists, on their 2006 album The Crane Wife.