During the Mexican–American War, she took part in expeditions against Alvarado, Tampico, Pánuco, and Laguna de Términos, all successful in tightening American control of the Mexican coastline and interrupting coastwise commerce and military supply operations.

Through the remainder of the war, Mississippi contributed guns, men, and boats to a series of coastal raids on Mexico's east coast, taking part in the capture of Tabasco in June 1847.

[citation needed] On 28 August 1851, Mississippi ran aground off Smyrna, Ottoman Empire whilst on her way to collect Louis Kossuth before taking him into exile in the United States.

As the flagship for Commodore Josiah Tattnall III, she was present during the British and French attack on the Chinese forts at Taku in June 1859, and two months later, she landed a force at Shanghai when the American consul requested her aid in restoring order to the city, torn by civil strife.

Mississippi arrived off Key West, Florida, to institute the blockade there on 8 June 1861, and five days later made her first capture, the schooner Forest King bound with coffee from Rio de Janeiro to New Orleans, Louisiana.

As Farragut brought his fleet up the river, a key engagement occurred at the Battle of Forts Jackson and St. Philip on 24 April 1862, during which Mississippi ran the Confederate ram Manassas ashore, wrecking her with two mighty broadsides.

Three of Mississippi's men, Seaman Andrew Brinn, Boatswain's Mate Peter Howard, and U.S. Marine Corps Sergeant Pinkerton R. Vaughn, were awarded the Medal of Honor for their actions during the abandonment.