On her first overseas cruise, Potomac departed New York 19 August 1831 for the Pacific Squadron via the Cape of Good Hope on the first Sumatran Expedition.

The frigate next made two cruises to the Brazil Station, protecting American interests in Latin America from 20 October 1834 to 5 March 1837, and from 12 May 1840 to 31 July 1842.

During this latter period, she landed troops at Port Isabel, Texas, on 8 May 1846 in support of General Zachary Taylor's army at the Battle of Palo Alto.

At the outbreak of the American Civil War, she departed from New York City on 10 September 1861 for the West Gulf Blockading Squadron off Mobile Bay.

At this time, William Thomas Sampson served aboard her until 25 December 1861 when he transferred to the USS Water Witch as executive officer.