Ordered upriver for the operations against Port Hudson, Louisiana, "Mississippi" sailed with six other ships lashed in pairs, while she sailed alone. On 14 March 1863, she grounded while attempting to pass the forts guarding Port Hudson. Under enemy fire, every effort was made to refloat her by Captain Melancton Smith and his executive officer George Dewey (later to achieve fame as an admiral). At last, her machinery was destroyed, her battery spiked, and she was fired to prevent Confederate capture. When the flames reached her magazines, she blew up and sank. 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. She lost 64 men, with the accompanying ships saving 223 of her crew.