Pocotaligo was eventually taken over by settlers, who established a bridge over the creek and allowed the community to be an important stop along the overland route between Charleston and Savannah.

Prior to the Civil War, Pocotaligo became an important stop on the Charleston and Savannah Railway, with a depot located about one mile northwest of the settlement.

When hostilities began in 1861 and the Federal capture of the Beaufort area in the Battle of Port Royal, control of the railway became an objective in disrupting the Confederate economy.

Pocotaligo was the closest depot to Port Royal Island and was a sought-after target for Union troops to disrupt rail service.

For a short time in 1862, General Robert E. Lee was assigned to South Carolina to protect the railway, establish defensive units, and prevent Union incursion onto the mainland from the Sea Islands.