Having spent nearly 13 years at sea, the decommissioned frigate St. Lawrence was quickly prepared for war in 1861, joining the North Atlantic Blockading Squadron. She sank a Confederate privateer and captured two blockade-runners in Hampton Roads, Virginia. On March 8, 1862, she encountered Virginia With two Union frigates already removed from the fray, St. Lawrence was towed toward the Confederate ironclad, grounding about 900 yards from her adversary. When rapid-firing guns failed to weaker her enemy, Virginia scored a telling hit near the waterline with an 80-pound shell. That night St. Lawrence re-floated and anchored under the safety of Fortress Monroe. After Hampton Roads she served briefly with the Potomac Flotilla, but returned to blockade duties between Florida and Cuba. In 1865 St. Lawrence returned to Virginia as a store ship. She ended her naval service as a Marine barracks before being sold in 1875.

Although obscure to most, the frigate's early service was filled with interesting deployments to Europe and South America. She was home to four Prussian midshipmen in 1848-1849 as part of the American assistance to a briefly united Germany. In 1851 St. Lawrence transported the American industrial products to London for the Crystal Palace Exposition. Seven years later, as flagship of the Brazilian squadron, she contributed to a successful U.S. effort to gain redress from Paraguay for the unprovoked firing upon USS Water Witch in 1855. She was equipped with a complement of 480 officers and men, eight 8-inch shell guns, and forty-two 32-pounder guns.