She was originally commissioned as USS Despatch – the second U.S. Navy ship of that name – on 17 January 1856, with Lieutenant T. M. Crossan in command, and was recommissioned and renamed in 1860, seeing action in the American Civil War.

Despatch, carrying naval passengers and cargo, departed New York on 4 April for the Gulf of Mexico, returned on 12 June, and decommissioned on 4 July for installation of improved boilers and condensers.

Arriving Vera Cruz on 16 April, she joined the Home Squadron and cruised along the Mexican coast protecting American citizens and commerce and carrying diplomatic despatches.

Departing Vera Cruz during the secession crisis, Pocahontas arrived Hampton Roads on 12 March, and on 5 April was assigned to the small joint Army-Navy force sent to Charleston Harbor to provision the federal garrison at Fort Sumter.

Assigned to the newly established South Atlantic Blockading Squadron, Pocahontas departed Washington on 15 October for Newport News, Virginia and sortied from Hampton Roads on the 29th with Flag Officer Samuel F. Du Pont's fleet.

At the battle, Pocahontas was apparently piloted into the anchored USS Seminole by its executive officer, a man who would later achieve international fame as a renowned naval theorist: Lt. Alfred Thayer Mahan.

She helped to capture Tybee Island, Georgia on 24 November and assisted in towing ships of the "Stone Fleet" to Maffitt's channel and sank them from 20–26 January 1862 to block the approaches to Charleston from the sea.