[4] Pickens County was part of Cherokee homeland territory until well after the American Revolution.

The Cherokee had allied with the British, hoping to gain expulsion of European-American settlers from their lands.

But they were defeated in local battles of the Revolution and forced to cede their lands under various treaties.

Streets for the county seat and courthouse town of Pickensville (near present-day Easley) were laid off.

New buildings perhaps included a large wooden hotel, which served as a stagecoach stop.

After a new courthouse was erected at Pendleton to accommodate the Court of General Sessions and Common Pleas, Pickensville began to decline.

In view of the growing population and poor transportation facilities in Pendleton District, the legislature divided it into counties in 1826.

A courthouse was established on the west bank of the Keowee River, and a small town called Pickens Court House soon developed here.

Since 1825, John C. Calhoun made his home in what became Pickens County, at Fort Hill, which became the basis around which Clemson University would later grow up.

Its small industry consisted mainly of sawmills, gristmills, and a few other shops producing goods for home consumption.

There was little organized troop combat here during the Civil War, but the district was frequently plundered by marauders and deserters who swept down from the mountains.

The South Carolina Constitutional Convention of 1868, meeting during the first year of Congressional Reconstruction, changed the name "district" to "county" throughout the state.

The convention also organized Oconee County, from a portion of Pickens District that was west of the Keowee and Seneca rivers, plus a small area around the Fort Hill estate formerly belonging to statesman John C. Calhoun.

Many of the residents of Old Pickens, on the Keowee River, moved to the newly created town, some relocating their dismantled homes.

The loss of the Oconee area greatly reduced the population of Pickens County.

Calhoun (now part of Clemson) was founded in the 1890s, to be followed in the early 1900s by Six Mile and Norris as incorporated areas.

A major factor in Pickens County's growth was the development of the regional textile industry, which had earlier been based in New England and New York.

The county's first modern cotton mill, organized by D. K. Norris and others, was established at Cateechee in 1895.

A notable change in the Pickens landscape was the coming of paved highways; one completed across the county, about 1930, ran from Greenville to Walhalla by way of Easley, Liberty, and Central.

[5] The most significant developments in the county's history have occurred since World War II.

By 1972 there were 99 manufacturing plants in the county, employing almost 15,000 personnel and producing not only textiles but a wide variety of other products.

[citation needed] According to an article written for Pickens County Heritage, new residents continue to be attracted to Pickens County "because of its climate, industrial opportunity, proximity to Greenville's labor market, and scenic beauty".

[6] The county also contains the highest natural point in South Carolina, Sassafras Mountain, with an elevation of 3,560 feet (1,090 m).

Jimmy Carter's narrow loss in 1980 is the last time that a Democrat has won even 40 percent of the county's vote.

[23] As of April 2024[update], some of the largest employers in the county include Aramark, the city of Clemson, Clemson University, Danfoss, Ingles, Lowe's, Merck & Co., Prisma Health, Publix, St. Jude Medical, and Walmart.