Santee NWR, established in 1941, is located in Clarendon County, South Carolina. Of the total 13,000 acres that make up the refuge, only 4,400 acres are owned with the remaining acreage being managed under a lease agreement with the South Carolina Public Service Authority (aka Santee-Cooper). The refuge also manages 10 conservation easements on private lands, totalling 458 acres in Bamberg, Barnwell, Clarendon and Orangeburg counties.

The refuge is located on the north shore of Lake Marion, the largest lake in South Carolina. It is a major wintering area for ducks and geese, as well as a nesting and stopover area for neo-tropical migratory birds, raptors, shore birds, and wading birds. Endangered/ threatened species on the refuge include the American alligator and the wood stork. Numerous other species of wildlife are indigenous to this area.

Public use opportunities at the refuge include a visitors center with educational exhibits, walking trails, an auto tour route, wildlife observation and photography, hunting, and fishing.

The Santee Indian Mound/Ft. Watson is located on the Bluff Unit of the refuge. This historic site is approximately 1000 years old and was a significant battle site during the Revolutionary War.

The mission of the National Wildlife Refuge System is to administer a national network of lands and waters for the conservation, management, and where appropriate, restoration of the fish, wildlife, and plant resources and their habitats within the United States for the benefit of present and future generations of Americans.

The Santee National Wildlife Refuge was established in 1941 to conpensate for the loss of critical migratory waterfowl habitat flooded in the Santee Cooper Lakes project. Over time, the refuge boundaries have changed, the current boundary 13,000 acres separated into 4 distinct units.