Pickens County is a county located in the northwest part of the U.S. state of South Carolina. As of the 2020 census, its population was 131,404. Its county seat is Pickens. The county was created in 1826. It is part of the Greenville-Anderson-Greer, SC Metropolitan Statistical Area.

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.

This former Cherokee territory was included in the new state's Ninety-Six Judicial District. In 1791 the state legislature established Washington District, a judicial area composed of present-day Greenville, Anderson, Pickens, and Oconee counties (the latter was not organized until 1868); at that time it also included Pendleton County.

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. In 1798 Washington District was divided into Greenville and Pendleton districts. The latter included what eventually became Anderson, Oconee, and Pickens counties. 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. But a year later, it decided to establish judicial districts instead. The legislation went into effect in 1828. The lower part became Anderson and the upper Pickens, named in honor of Brigadier General Andrew Pickens of the American Revolution. His home, Hopewell, was on the southern border of the district. 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.

By 1860 Pickens District had a population of more than 19,000 persons, of whom 22 percent were enslaved African Americans. The district was largely rural and agricultural, with cotton the most important commodity crop. Its small industry consisted mainly of sawmills, gristmills, and a few other shops producing goods for home consumption. The district's Protestant churches were numerous, but schools were few. The Blue Ridge Railroad reached the district in September 1860. 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.

After the war, the region was largely destitute. 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. In the 1960s, this small area around the Calhoun property was transferred to Pickens County.

A new courthouse for Pickens County was erected at its present location. 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. It did not again reach 19,000 until 1900.