[1] Susquehanna joined Commodore Matthew Perry's expedition as his flagship at Canton and entered Edo Bay with his squadron on 8 July 1853.

On 12 February 1854, Susquehanna returned with the squadron to Japan as part of Perry's show of force, resulting in the signing of the Convention of Kanagawa on 31 March 1854.

The frigate departed Japanese waters on 24 March; and, after operating on the China coast, headed home via the Indian Ocean and the Cape of Good Hope.

Late in October, Susquehanna joined Flag Officer Samuel Francis DuPont's expedition to South Carolina waters which captured Port Royal Sound on 7 November; took possession of Beaufort, South Carolina, on 9 November; and established a blockade at the mouth of the Broad River the same day.

On 27 April, Susquehanna was ordered to Hampton Roads to strengthen the North Atlantic Blockading Squadron which was then making every effort to support Major General George B. McClellan's drive up the peninsula toward Richmond, Virginia.

Susquehanna and four other Union warships acting under orders from President of the United States Abraham Lincoln bombarded Confederate batteries at Sewell's Point, Virginia, on 8 May.

Three days later, Virginia was blown up by her crew, ending her threat to Union shipping in the Hampton Roads area and freed Susquehanna for duty elsewhere.

When the Susquehanna found out that the acting imperial ruler Maximilian I of Mexico had decided not to abdicate, the ship turned around to head home 1866.

[3] The USS Susquehanna also sailed for Brazil and operated on the Atlantic coast of South America until returning home and decommissioning on 30 June 1866.