During the American Civil War, in July 1861, "Preble" joined the Gulf Blockading Squadron and participated to the blockade of the Mississippi River. She was posted at Head of the Passes on the Mississippi River on 12 October 1861 when the blockading squadron there was attacked by a Confederate States Navy force that included the first ironclad warship, CSS "Manassas". Being a-sail-powered ship, she did not join the battle but rather made a swift retreat out the Southwest Pass to safety in the Gulf of Mexico.