Cherokee Indians lived in this region long before the American Revolution. It was the Cherokee's choice to side with Great Britain during the war for independence, which led to the loss of their land in what is now the northwestern corner of South Carolina.

Two months of fighting in the summer of 1776 between the Patriot militia and the Cherokees, aided by Loyalists, brought Indian defeat. By 1789, this region became Pendleton County within the overarching Ninety-Six District. Today this area is Anderson, Oconee and Pickens counties, but a common bond remains. 

By 1791, there were significant enough numbers of white settlers in the previously-held Cherokee lands that the new state of South Carolina finally decided to officially recognize that these settlements were going to need state and local governmental supervision. In that year, two new Districts were created in the northwestern section of South Carolina - the Pinckney District and the Washington District. Each had District Seats designated with courts established in those seats. Washington District would include the recently created "new counties" of Greenville County (created in 1786) and Pendleton County (this county, created in 1789).

In 1798, the recently-established Washington District was abolished and renamed as the overarching Pendleton District. Pendleton District now included Pendleton County and Greenville County, but the "overarching" Pendleton District was short-lived. In 1800, all "overarching Districts" were abolished for good, leaving only "counties" as the governmental unit - even though the state of South Carolina continued to call them "districts" until 1868, when they finally abandoned the term "district" and began using the term "county" from that point forward.

Although the "over-arching" Pendleton District was now gone in 1800, the "small district" (what we normally mean by county) continued in existence until 1826. In that year, Pendleton District (county) was abolished and split into two "new counties" - Pickens and Anderson. Since that time, the name Pendleton District/County has no longer been used in the state of South Carolina.