The 22nd Pennsylvania Cavalry was sent to Maryland for training, after which it was assigned to the Department of West Virginia.

A detachment of the regiment, under the command of Major George T. Work, fought in the Battle of Moorefield on August 7, 1864.

The regiment fought in several skirmishes during the Lynchburg Campaign and Early's Raid on Washington.

In August, it was assigned to the Army of the Shenandoah as part of the 3rd Brigade, Cavalry Corps.

In December, it was sent back to the Department of West Virginia, where it spent the remainder of the war chasing down guerrillas.