USS Cairo, a 512-ton "City" class ironclad river gunboat built at Mound City, Illinois, was commissioned in January 1862 as part of the U.S. Army's Western Gunboat Flotilla. She began war operations in February, taking part in the occupations of Clarksville and Nashville, Tennessee. In April and May 1862, Cairo was involved in the campaign to capture Fort Pillow and was present during the 10 May naval action there. She was also engaged with Confederate warships during the action off Memphis, Tennessee, on 6 June 1862.

Cairo continued her operations on the Mississippi River and its tributaries and was formally transferred to the Navy in October. On 12 December 1862, while engaged in mine clearance activities on the Yazoo River, Mississippi, Cairo was sunk by a Confederate mine (or "torpedo", as mines were then known). Her wreck was recovered in 1965, but was badly damaged during the salvage efforts. It has subsequently been partially restored and is on exhibit at Vicksburg, Mississippi.