Shakedown cruises took the new screw frigate to the Caribbean and to Western Europe. Merrimack visited Southampton, Brest, Lisbon, and Toulon before returning to Boston and decommissioning 22 April 1857 for repairs. Recommissioning 1 September 1857, Merrimack got underway from Boston Harbor 17 October as flagship for the Pacific Squadron. She rounded Cape Horn and cruised the Pacific coast of South and Central America until heading for home 14 November 1859. Upon returning to Norfolk, she decommissioned 16 February 1860.
Merrimack was still in ordinary during the crisis preceding Lincoln's inauguration. Soon after becoming Secretary of the Navy, Gideon Welles took action to prepare the frigate for sea, planning to move her to Philadelphia. The day before the firing on Fort Sumter, Welles directed that "great vigilance be exercised in guarding and protecting" Norfolk Navy Yard and her ships. On the afternoon of 17 April 1861, the day Virginia seceded, Engineer in Chief B. F. Isherwood managed to get the frigate's engines lit off; but the previous night secessionists had sunk light boats in the channel between Craney Island and Sewell's Point, blocking Merrimack. On the 20 April, before evacuating the Navy Yard, the U.S. Navy burned Merrimack to the waterline and sank her to preclude capture.