As part of the Army of Northern Virginia, the 2nd Regiment fought in many of the most decisive battles of the Eastern theater of the American Civil War, suffering heavy casualties at Antietam and Gettysburg.

After spending the winter in camp, in April 1862 the 2nd Mississippi was moved to Yorktown, Virginia and reorganized, as the Regiment's initial one-year term of service had expired.

At the Battle of Gaines' Mill, the 2nd Mississippi joined an advance alongside John Bell Hood's Texas Brigade that broke through the Union lines, resulting in a Confederate victory.

Subsequently, the 2nd Mississippi fought at the Battle of Antietam in September, where they were engaged in some of the heaviest fighting on the bloodiest day of the war.

[1] After Antietam, the 2nd Regiment was reassigned to General Joseph R. Davis's Mississippi brigade and took part in the Siege of Suffolk before moving north to Pennsylvania during the Gettysburg Campaign.

On the opening day of the battle, the 2nd Mississippi was among the first Confederate troops to engage Union forces, coming into contact with General John Buford's cavalry along the Chambersburg Pike to the northwest of the town of Gettysburg.

[1] Afterwards, the Regiment was moved to support the Confederate defensive lines during the Siege of Petersburg, fighting in numerous engagements until the fall of the city to Union forces in late March, 1865.