Waccamaw NWR was established on December 1, 1997. The purposes for which it was established were to (1) protect and manage diverse habitat components within coastal river ecosystems for the benefit of endangered and threatened species, freshwater and anadromous fish, migratory birds, and forest wildlife, including a wide array of plants and animals associated with bottomland hardwood habitats; and (2) provide a variety of wildlife-dependant recreational activities including hunting, fishing, wildlife observation, photography, & environmental education.

Located in portions of Horry, Georgetown, and Marion Counties, Waccamaw NWR's acquisition boundary spans over 55,000 acres and includes large sections of the Waccamaw & Great Pee Dee rivers and a small section of the Little Pee Dee River. An active land acquisition program from willing sellers within the boundary is ongoing.

Presently Waccamaw National Wildlife Refuge encompasses nearly 27,000 acres. In 2008 Waccamaw NWR opened the newly constructed Cox Ferry Lake Recreation Area and has also opened a new state-of-the-art Visitor & Environmental Education Center on Highway 701 north of Georgetown.

Waccamaw NWR is one of four refuges in the South Carolina Lowcountry Refuges Complex. Other refuges in the Complex include: Ernest F. Hollings ACE Basin NWR, Cape Romain NWR, & Santee NWR.