The regiment went through a series of reassignments; first in November 1862 to Gilbert's Command, District of Western Kentucky, Department of the Ohio.

While in Franklin, Tennessee, in February 1863 the regiment was assigned to the Army of Kentucky, Department of the Cumberland.

In June 1863, another reassignment assigned the 78th Illinois to the 2nd Brigade, 1st Division Reserve Corps, Army of the Cumberland.

The final reorganization would come in October 1863, assigning the regiment to the 2nd Brigade, 2nd Division, XIV Corps.

[1]: 6 Companies B and C were captured by, then Colonel, John Hunt Morgan during a December 26, 1862, raid at Muldraugh Hill.

They were sent to St. Louis, Missouri, under terms of parole and not exchanged until October 1863, effectively reducing the regiment by two companies of infantry.