She departed Hampton Roads on 25 June 1845 as flagship of Commodore Charles W. Skinner in command of United States naval vessels operating off the western coast of Africa to suppress the slave trade.

While she was moored at the Boston Navy Yard word reached the United States that for the second consecutive year blight had ruined the potato crop of Ireland, depriving the people of that country of their chief means of subsistence.

A joint resolution of Congress approved 3 March 1847 authorized the Secretary of the Navy to place Jamestown and Macedonian at the disposal of Captains Robert Bennet Forbes and George Coleman De Kay to carry food to the starving poor of Ireland.

A year later she was transferred to the Mediterranean Squadron to assist in protecting American citizens and interests during the epidemic of revolutions which convulsed Europe in 1848.

After a year at home, she was assigned to the Brazil Squadron departing Norfolk on 1 June 1851 to begin operations off South America lasting until her return to Philadelphia Navy Yard on 2 May 1854.

After the outbreak of the Civil War, Jamestown re-commissioned on 5 June 1861 and was assigned to the Atlantic Blockading Squadron, where she compiled a record of outstanding efficiency.

Jamestown departed for the Pacific on 12 October to protect American commerce from Confederate privateers; and she remained on that duty until after the end of the war, decommissioning at Mare Island on 17 September 1865.

While at the Brooklyn Navy Yard on 20 December 1883, Landsman J. W. Norris and Ordinary Seaman Robert Augustus Sweeney jumped overboard and rescued a man from drowning, for which they were each awarded the Medal of Honor.