After garrison duty in Missouri, the regiment served in Gen. Ulysses S. Grant's Vicksburg Campaign of 1863 as part of the XIII Corps.

The regiment was one of the first ashore in Mississippi after the river crossing on April 30, 1863, and was the only Union unit to breach the defenses of Vicksburg, MS, at the Railroad Redoubt, during the general assault of May 22, 1863.

The 22nd was one of only three regiments from Iowa to serve in Virginia, including during Gen. Philip Sheridan's Shenandoah Valley Campaign of August–November 1864.

Sergeant Leonidas M. Godley of Company E was awarded the Medal of Honor in 1894 for his actions during the assault on the Railroad Redoubt, outside Vicksburg, on May 22, 1863.

Samuel D. Pryce, delegate to first GAR convention; author of regimental history, Vanishing Footprints: The Twenty-Second Iowa Volunteer Infantry in the Civil War.