From 1855–1858 Constellation performed largely diplomatic duties as part of the US Mediterranean Squadron.

She was flagship of the African Squadron from 1859–1861. In this period she disrupted the African slave trade by interdicting three slave ships and releasing the imprisoned Africans.

• On 21 December 1859, she captured the brig Delicia which was "without colors or papers to show her nationality completely fitted in all respects for the immediate embarcation of slaves..."
• On 26 September 1860, Constellation captured the "fast little bark" Cora with 705 slaves, who were set free in Monrovia, Liberia.
• On 21 May 1861, Constellation overpowered the slaver brig Triton in African coastal waters. It held no slaves, although "every preparation for their reception had been made."
  

Constellation spent much of the war as a deterrent to Confederate cruisers and commerce raiders in the Mediterranean Sea.

After the Civil War, Constellation saw various duties such as carrying famine relief stores to Ireland and exhibits to the Paris

Decommissioned in 1933, Constellation was recommissioned as a national symbol in 1940 by President Franklin Roosevelt; by this time the ship had become widely confused with her famous predecessor of 1797. She spent much of the Second World War as relief (i.e. reserve) flagship for the US Atlantic Fleet, but spent the first six months of 1942 as the flagship for Admiral Ernest J. King and Vice Admiral Royal E. Ingersoll.

Constellation was again decommissioned on 4 February 1955, and stricken from the Naval Vessel Register on 15 August 1955 – about 100 years and two weeks from her first commissioning. She was taken to her permanent berth – Constellation Dock, Inner Harbor at Pier 1, 301 East Pratt Street, Baltimore, Maryland and designated a National Historic Landmark on 23 May 1963, and she was placed on the National Register of Historic Places on 15 October 1966. She is the last existing intact naval vessel from the American Civil War, and she was one of the last wind-powered warships built by the US Navy. She has been assigned the hull classification symbol IX-20.

In 1994 Constellation was condemned as an unsafe vessel. She was towed to a drydock at Fort McHenry in 1996, and her $9 million restoration project was completed in July 1999.

On 26 October 2004, Constellation made her first trip out of Baltimore's Inner Harbor since 1955. The trip to the U.S. Naval Academy in Annapolis lasted six days, and it marked her first trip to Annapolis in 111 years.

Tours are regularly available, self-guided or with the assistance of staff. Nearly all of the ship is accessible, and about one-half of the lines used to rig the vessel are present (amounting to several miles of rope and cordage). A cannon firing is demonstrated daily, and tour groups can also participate in demonstrations such as "turning the yards" and operating the capstan on the main deck to raise/lower cargo.

The ship is now part of Historic Ships in Baltimore.