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The district was occupied for thousands of years by succeeding cultures of indigenous peoples. By the time of European encounter, Siouan-speaking tribes, such as the Pee Dee, Cheraw and Catawba, inhabited the Piedmont area above the fall line.

The Orangeburg Judicial District was chartered by European Americans in 1769 from a mostly unorganized upland area between the Congaree and Savannah rivers. A county, initially of the same name but later called Orange, was organized within the district but de-organized in 1791, after the American Revolutionary War.

The southwest portion bordering on the Savannah River, about half of Orangeburg District, was separated and organized as Barnwell District in 1800. In 1804 the northern third of the district was separated to form the new Lexington District, which gained another, smaller portion of Orangeburg District in 1832.

During the nineteenth century, the districts and counties were developed chiefly as cotton plantations for short-staple cotton. This development followed the invention of the cotton gin in the late eighteenth century, which made the processing of short-staple cotton profitable. The county became a center of labor by black slaves on the plantations, who were transported from coastal areas and the Upper South to cultivate and process cotton. Those brought from the coastal areas were likely of the Gullah culture and language. The enslaved African Americans greatly outnumbered the white planters and non-slaveholding whites. Reflecting the patterns of nineteenth-century settlement, the area is still chiefly agricultural and majority-African American in population.

In 1868, under the revised state constitution during the Reconstruction era, South Carolina districts were organized as counties. Resident voters were enabled to elect their state representatives rather than having them chosen by the state legislature, as was done previously. Election of representatives by the state legislature had kept the districts dominated by the elite owners of major plantations in the Low Country and elsewhere. The changes in rules expanded participation in the franchise by more male residents. Emancipation of slaves after the war under newly ratified federal constitutional amendments resulted in freedmen voting. Using voter intimidation, white Democrats took control of the state legislature by the end of the century; they passed state electoral laws and a new constitution that essentially disfranchised most blacks, a situation that lasted until after the federal legislation of the 1965 Voting Rights Act.