The Little Salkehatchie River originates in the Town of Blackville, South Carolina and accepts drainage from Lake Cynthia, Guess Pond, Brooker Pond, Ghants Branch, Halfmoon Branch, and Long Gall Branch. Further downstream, the river accepts drainage from Long Pond, Ben Rice Bay, Colston Branch (Ben Rice Branch, Doussoss Bay, Indian Camp Branch, McMillian Branch), and Long Branch (Little Clear Pond, Clear Pond). There are a total of 111.7 stream miles and 397.4 acres (1.608 km²) of lake waters in this watershed, all classified freshwater.