European settlement in this area started in 1704 when George Sterling set up a post here for fur trade with Native Americans.

To encourage settlement, the General Assembly of the Province of South Carolina in 1730 organized the area as a township, naming it Orangeburg for William IV, Prince of Orange, the son-in-law of King George II of Great Britain.

In 1735, a colony of 200 Swiss, German and Dutch immigrants formed a community near the banks of the North Edisto River.

The river provided the all-important transportation waterway to the port of Charleston on the Atlantic coast for the area's agriculture and lumber products, and for shipping goods upriver.

The church building was erected prior to 1763 in the center of the village; it was destroyed by fighting during the Revolutionary War.

A new church was built; during the Civil War, it was used as a smallpox hospital by General William Tecumseh Sherman on his march through with Union forces.

It was easily grown in the upland areas, and the county was rapidly developed into large cotton plantations.

Efforts by blacks to regain civil rights increased in the postwar period after World War II.

In 1960, over 400 students were arrested on sit-ins and integration marches organized by the Congress of Racial Equality (CORE).

Local efforts to end segregation in public places continued, particularly after Congress passed the Civil Rights Act of 1964.

Police opened fire on a crowd of students, killing Samuel Hammond, Henry Smith, and Delano Middleton, and wounding 27 others in what became known as the "Orangeburg Massacre".

In 2021, President Joe Biden visited Orangeburg to deliver a commencement address at South Carolina State.

The climate in this area is characterized by relatively high temperatures and evenly distributed precipitation throughout the year.

The Museum and Planetarium is located on the campus of South Carolina State University and signifies their commitment to community service.

The building is easily accessible to the handicapped and is a uniquely adaptable facility, capable of hosting many different types of presentations.

During the winter in Orangeburg, more festivities get under way when raccoon hunters from throughout the Southeast gather for the Grand American Coon Hunt.

The following notable buildings and districts are listed on the National Register of Historic Places:[20] Media related to Orangeburg, South Carolina at Wikimedia Commons