A strong backer of national government, Drayton was on duty at the naval yard in Philadelphia during the secession crisis. To show his loyalty, he requested in February 1861 that his nativity on the naval register be changed from South Carolina to Pennsylvania. His favoring of the national government was declared "infamous" by the South Carolina legislature. For the first months of the war Drayton supervised the outfitting of vessels at Philadelphia until September 1861, when he applied for sea duty with the squadron being organized by Captain Samuel Francis Du Pont. Assigned to the gunboat Pocahontas, Drayton commanded the vessel during Du Pont's attack on the Confederate fortifications at Port Royal, South Carolina, which were commanded by his older brother Thomas F. Drayton.
The day after the battle of Port Royal Percival Drayton was given command of the gunboat Pawnee and with that vessel carried out reconnaissance missions in the region's rivers and sounds, securing enemy forts and liberating slaves. Besides believing slaves could be seized as contraband, Drayton also considered slavery a disgrace to civilization. His experiences along the southeastern coast convinced him that freed slaves would become productive citizens. He participated in expeditions against Fernandina, Florida, and St. Marys, Georgia, and on 28 May 1862 Drayton commanded the naval squadron that entered the Stono River, and later he directed his vessels in support of the army in June and July during the Secessionville campaign.