This department existed in three separate periods. This department was created on May 3, 1861. It was geographically defined by the states of Ohio, Indiana, and Illinois. On May 9, 1861, the department was expanded to include portions of Western Virginia, Pennsylvania, and Maryland. The department was reconfigured to include Indiana, Ohio, and a portion of Western Virginia, removing the state of Illinois and portions of Pennsylvania and Maryland. On September 19, 1861, the department was redefined as the states of Indiana and Ohio, and the area of Kentucky within fifteen miles of Cincinnati, Ohio. And on November 9, 1861, the department was redefined as the states of Ohio, Michigan, Indiana, Tennessee, and the portions of Kentucky east of the Cumberland River. This department was disbanded on March 11, 1862 and combined with the Mountain Department and the Department of the Mississippi. Commander(s): George B. McClellan, William S. Rosecrans, Ormsby M. Mitchel, and Don Carlos Buell.

The second was created on August 19, 1862. It was geographically defined as the states of Illinois, Indiana, Michigan, Ohio, Wisconsin, the portion of Kentucky east of the Tennessee River, and inclusive of Cumberland Gap and all Federal forces operating in its vicinity. Wisconsin transferred to the Department of the Northwest on September 6, 1862. On September 19, 1862, Alton, Illinois transferred to the Department of Missouri and all of Western Virginia joined the Department of the Ohio. Cairo, Illinois transferred to the Department of the Tennessee on October 16, 1862. On March 16, 1863, all of Western Virginia moved to the Middle Department. Gallipolis, Ohio and the Ohio shoreline opposite the mouth of Kanawha River joined the Middle Department on June 9, 1863. On June 9, 1863, Columbiana, Jefferson, and Belmont Counties in Ohio joined the Department of the Monongahela. On June 23, 1863, Monroe, Athens, Washington, Meigs, Gallia, and Lawrence Counties in Ohio joined the Middle Department. The department joined the Military Division of the Mississippi on October 16, 1863, joining the Departments of the Cumberland and the Tennessee. On November 16, 1863, the department was reconfigured to include the portions of Kentucky east of the Tennessee River and parts of East Tennessee under the control of the Army of the Ohio. Jeffersonville, Indiana joined the department on February 8, 1864. Covington, Kentucky and the surrounding fifteen mile radius joined the Northern Department. This department was disbanded on January 17, 1865 and joined the Department of the Cumberland. Commander(s): Horatio G. Wright, Ambrose E. Burnside, John G. Foster, John M. Schofield, and George Stoneman.

The third was created on June 27, 1865. It was geographically defined as the states of Illinois, Michigan, Ohio, and Indiana, with the exception of Jeffersonville and New Albany, Indiana. The state of Wisconsin was added to the department on October 30, 1865. On June 5, 1866, the Department of Kentucky—along with Jeffersonville and New Albany, Indiana—were added to the department. This department was disbanded on August 6, 1866 and consolidated into the Department of the Lakes. Commander(s): Edward O. C. Ord and Orlando B. Wilcox.