Formed in August 1861, the regiment served in the Western Theater of the American Civil War and was unique in that there were 12 companies.

In 1864, the regiment fought in the Meridian, Atlanta, and Franklin–Nashville campaigns, suffering heavy losses at Peachtree Creek and Franklin.

On 7 November 1861, the regiment was sent to the west bank of the Mississippi River to help in the Battle of Belmont but by the time it arrived, the fighting had ended.

The regiment also guarded Holly Springs, Mississippi, and Port Hudson, Louisiana, before returning to Grenada.

In February 1863, the unit returned to Port Hudson and was there when the Union Navy attacked the place on 14 March.

The regiment traveled to Atlanta but was ordered back to Mississippi to stop Grierson's Raid, in which it was unsuccessful.

[7] A 160-man detachment from the 12th Louisiana Infantry led by Captain Dixon (Company C) fought in the Siege of Vicksburg (18 May–4 July 1863) as part of Brigadier General John C. Vaughn's brigade.

[3] From 3 February to 5 March 1864, Major General William Tecumseh Sherman and 25,000 Union soldiers took part in the Meridian campaign.

[11] In the Atlanta campaign, the 12th Louisiana Infantry was assigned to Scott's brigade, Loring's division, Polk's corps.

[12] At the Battle of Peachtree Creek on 20 July 1864, Scott's brigade attacked Brigadier General John W. Geary's Union division.

At the first onset, Scott's men overwhelmed the 33rd New Jersey Infantry Regiment, which was holding an advanced outpost, capturing its flag and many soldiers.

Following an unguarded ravine, Scott's troops gained the rear of the Union front line, panicking many soldiers, and overrunning a 4-gun battery.

However, Geary's reserve brigade and rallied Federal soldiers counterattacked; they drove Scott's men back after bitter fighting.

[17] At Bentonville, the 12th Louisiana Infantry under Lieutenant Colonel Graham was assigned to Brigadier General Robert Lowry's brigade, Loring's division, Stewart's corps.