USS Mississippi CDVMississippi 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. On 27 November 1861, off Northeast Pass of the Mississippi River, she joined Vincennes in capturing the British bark Empress, again carrying coffee from Rio to New Orleans. The following spring, she joined Farragut's squadron for the planned assault on New Orleans. 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. One of her sailors, seaman Christopher Brennan, was awarded the Medal of Honor for his part in the battle. The city was now doomed, and Mississippi, her heavy draft making her less suitable to river operations than lighter ships, remained off New Orleans for much of the next year.

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 set ablaze 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.