At the start of the Civil War, McCook was appointed colonel of the 1st Ohio Infantry in April 1861. He served in the Washington defenses and saw action at the First Battle of Bull Run. On September 3, 1861, he was promoted to brigadier general of volunteers and commanded a division in Tennessee. He earned the brevet of lieutenant colonel in the regular army for his part in the capture of Nashville, Tennessee. McCook then commanded the 2nd Division in the Army of the Ohio at the Battle of Shiloh on the second day of fighting, and then in the subsequent campaign against Corinth. He was promoted to major general of volunteers on July 17, 1862.