It received its final designation when it was transferred to the Union Navy at the beginning of October 1862.

Flag Officer Andrew H. Foote relieved Rodgers and encouraged the army commander in the west, Major General Henry W. Halleck, to authorize an expedition down the Tennessee River against Fort Henry.

The U. S. Ram Fleet, commanded by Colonel Charles Ellet, Jr., accompanied the squadron during the First Battle of Memphis.

Rear Admiral David D. Porter relieved Davis in command and led the squadron at Arkansas Post and during the successful Vicksburg Campaign and siege of the city.

During the Red River Campaign, the Mississippi Squadron was composed of 10 ironclads, 3 monitors, 11 tin-clads, 1 timber-clad, 1 ram and various support vessels, including vessels in the following table: Command temporarily passed to Alexander Pennock before Samuel P. Lee assumed command.