Necessary alterations and repairs and lack of sufficient water to pass over the falls detained her in the Ohio River until early January 1863.

From 8 January 1863, when she sailed from Cairo, Illinois, until the end of the American Civil War, Chillicothe was constantly employed in the Mississippi River and its tributaries.

Coming under enemy's fire with Baron DeKalb in the Yazoo expedition, Chillicothe was heavily damaged and lost several men.

On 24 February 1864 she entered the Red River for the expedition of 7 March to 15 May in which her commanding officer, Lieutenant Joseph P. Couthouy, was mortally wounded by rifle fire on 3 April.

From 22 May 1864 until 26 May 1865 she lay off Fort Adams, Mississippi, on 8 June 1864 assisting in the capture of a Confederate battery at Simmesport, Louisiana.