She served as flagship of the Home Squadron in the late 1850s and captured several Confederate ships after the start of the American Civil War in 1861.

Her deep draft meant that she could not operate off shallow Confederate ports and she was relegated to harbor defense at Hampton Roads, Virginia for the duration of the war.

The engine produced a total of 996 indicated horsepower (743 kW) and the ship had a maximum speed of 8.8 knots (16.3 km/h; 10.1 mph) under steam alone.

[5] Assigned to the Home Squadron as flagship, Roanoke transported the American filibuster and former President of Nicaragua, William Walker, and his men back to the United States from Aspinwall, Colombia, (now called Colón, Panamá).

For over a year, she was stationed at Aspinwall awaiting the arrival of the first Japanese embassy to the United States to ratify the 1858 Treaty of Amity and Commerce.

[5] After the start of the Civil War, Roanoke recommissioned on 20 June 1861 and was assigned to the North Atlantic Blockading Squadron.

[5] Roanoke's deep draft prevented her from engaging the Confederate casemate ironclad CSS Virginia (her former sister USS Merrimack) during the Battle of Hampton Roads on 8–9 March 1862.

[5] On 19 March 1862, 10 days after the Battle of Hampton Roads where the Monitor fought the Confederate ironclad Virginia to a standstill, John Lenthall, Chief of the Bureau of Construction and Repair, and the Chief of Steam Engineering, Benjamin F. Isherwood, wrote a letter to Gideon Welles, the Secretary of the Navy recommending that Roanoke be converted into a seagoing ironclad as that would be cheaper and faster than new construction.

Aside from reinforcing her hull to carry the weight of the turrets, the only other changes that they recommended were the elimination of the hoisting screw, replacement by a propeller smaller in diameter, and the addition of a ram.

The deck armor was to be 2.5-inch (64 mm) thick and an additional steam engine would be necessary to rotate the turrets and run the ventilation fans.

[6] Welles accepted their recommendation and Roanoke began her reconstruction at the Brooklyn Navy Yard when she arrived in New York City on 25 March.

[11] Ignoring pressure by local politicians to keep Roanoke in New York, the Navy ordered her to Hampton Roads, Virginia, to join the blockading squadron there.

Captain Benjamin F. Sands reported that the ship's roll was so great that it would "preclude the possibility of fighting her guns at sea, and I was obliged to secure them with pieces of timber to prevent them fetching away".

[5] On 14 July, Sands test-fired his guns for the first time and both of the 15-inch Dahlgrens and one 150-pounder Parrott rifle dismounted themselves by their violent recoil.

Roanoke was reduced to reserve again on 12 June 1875; an assessment of her condition in 1876 noted that "this ship requires rebuilding with iron frame and plating".