Assigned to the African Squadron, Mohican departed Portsmouth on 19 January 1860 for the South Atlantic and for the next year and one-half cruised on patrol against pirates and slavers off the coasts of Africa and at times Brazil.

On 8 August, the sloop captured the slaver Erie — commanded by Nathaniel Gordon — off the Congo and forced that ship to unload its captive cargo at Monrovia, Liberia.

Following her arrival at Boston, Massachusetts on 27 September, she sailed to join Flag Officer Samuel Du Pont's South Atlantic Blockading Squadron off Sandy Hook, New Jersey.

Departing Norfolk, Virginia on 29 October for Port Royal, South Carolina, as part of the largest U.S. naval squadron assembled to that time, the sloop steamed in the battleline on 7 November as Du Pont's squadron pounded Fort Walker on Hilton Head Island, forcing the Confederates to abandon the emplacement, thereby allowing a combined Union Army and Navy Force to land and occupy this important base of operations.

The steamer sailed to Charleston Bar at the end of November accompanying part of the "Stone Fleet", and stood by while these ships were scuttled on 18–19 December to obstruct channels to Confederate ports in the Carolinas and Georgia.

The warship then operated off the southern coast with steamer USS Bienville, searching for Confederate shipping, capturing British blockade runner Arrow off Fernandina, Florida on 25 February 1862.

Mohican remained on the Pacific coast through 1872, cruising to South America in the fall and winter of 1867 and then decommissioning from 3 April 1868 – 7 June 1869 at Mare Island Navy Yard.