Later that month, Sprague was appointed as the colonel of the newly designated 63rd Ohio Infantry, The regiment was organized on January 23 by consolidating partially filled battalions from the 22nd Ohio Infantry and the 63rd Ohio regiments. After brief training and drilling, Sprague and his men took the field, traveled via train to the South, and joined Major General John Pope in Missouri. Sprague led the regiment at the Siege of Corinth, Mississippi, and then was in charge of the Ohio Brigade during the Battle of Iuka in 1862.