McCook enlisted in the 2nd Ohio Infantry, a three-months regiment, and was commissioned as a captain. He saw combat at the First Battle of Bull Run in Northern Virginia. When the regiment was reorganized as a three-years regiment, McCook re-enlisted and was named as major. He was subsequently promoted to lieutenant colonel and then colonel of the 2nd Ohio, serving in the Army of the Cumberland. Among his battles were Perryville, Stones River, Lookout Mountain and Missionary Ridge. During the Atlanta Campaign, McCook commanded a brigade of infantry and was distinguished by his actions at the Battle of Peachtree Creek, where his coolness under fire and his tactical leadership won acclaim in the official reports. He was mustered out in late 1864, along with his regiment.