[1] It first served in Mobile, Alabama; from there it was ordered to Corinth, Mississippi, and reached Tennessee in time for the Battle of Shiloh, where it suffered severe loss.

It took a very brilliant part in the impetuous assault on Rosecrans' army at the Battle of Chickamauga, 20 September, and suffered severely, losing almost two-thirds of its forces, the killed including five color-bearers.

At Shiloh, Captain Abner C. Gaines was fatally wounded and Major R. B. Armistead was killed.

During August 1862 the 1st Brigade (and Army of Mississippi, under Bragg) was loaded into railcars at Saltillo & Tupelo and were transported south by the Mobile and Ohio Railroad to Mobile, changed trains, and transported north to Montgomery, West Point, Atlanta, then Chattanooga.

From 31 December to 2 January 1863 the regiment fought fiercely in the Battle of Murfreesboro (also called Stone's River).

After ferocious, bloody fighting in the Battle of Murfreesboro, ten gallant men from the 22nd Alabama were inscribed into the Confederate Roll of Honor:[3] Following the battle, 1st Brigade retreated to Shelbyville, Tennessee, where it was joined later by the rest of the Army of Tennessee.

The 22nd Alabama was in the line of battle which moved to assault Union Major General William Rosecrans at Chickamauga, where it lost 5 color bearers and 175 killed and wounded out of about 400 engaged.

The 22nd Alabama lost lightly in November 1863 at the Battle of Missionary Ridge and wintered at Dalton, Georgia, where weather and sickness claimed 272 men.

The 22nd Alabama under the command of General George D. Johnston of Perry County, participated in the campaign from Dalton to Atlanta, losing gradually by the constant fighting.

It moved into Tennessee with General John Bell Hood and suffered severely at Franklin and lightly at Nashville.

The 22nd Alabama was transferred beyond the Edisto and moved into North Carolina, skirmishing with the advance of Union Major General George Thomas' army.

Rouse (Butler) as lieutenant colonel, and Robert Donald (Limestone) as major, and then surrendered at Greensboro, North Carolina, on 26 April 1865.