Leaving Illinois behind, the 106th took a train from Lincoln to St. Louis, Missouri, and thence to Columbus, Kentucky, where it was attached to the Army of the Tennessee under Major General Ulysses S. Grant.

After Forrest's raid, the regiment was assigned to guard railroad stations north of Jackson until May 31, 1863, when it was ordered to Vicksburg, Mississippi, to participate in the siege already taking place there.

Toward the end of the siege, they were transferred to the Yazoo River to protect the army's flank and rear against enemy raiders operating north of Vicksburg.

After the surrender of the Confederate bastion on July 4, 1863, the 106th was transferred to Helena, Arkansas, under the command of Major General Frederick Steele.

The report of the Illinois Adjutant General sums up the 106th Illinois' service succinctly: "Except the siege of Vicksburg, the Regiment was not in any of the most noted battles, but, nevertheless, it performed well its part in putting down a rebellion, and it suffered many privations and hardships marching through swamps and bayous, guarding railroads, government property, fighting and foraging, as is proven by its long list of casualties."