When the Civil War erupted, McCook recruited a company and joined the 31st Illinois Infantry, serving under his friend, Col. John A. Logan. He saw action in the battles of Fort Henry and Fort Donelson, where he was severely wounded. He was later assigned to command Logan's brigade when the latter assumed division command. By the Vicksburg Campaign, McCook had again been promoted to replace Logan as division commander, leading it during the Siege of Vicksburg under Ulysses S. Grant. In 1864, he served with distinction in the Chattanooga and Atlanta campaigns and in the March to the Sea under William T. Sherman. He was severely wounded three separate times but survived the war.