After a defeat at the Battle of Big Black River Bridge, the regiment took part in the siege of Vicksburg, where it saw heavy fighting.

The 6th Missouri Infantry was mustered on August 26, 1862, at Guntown, Mississippi, as the result of consolidation of several existing units.

[1] On the date of muster, the regiment's original organization was:[2] Companies "A", "B", "C", "E", "F", "G", and "H" contained men from Erwin's Battalion.

The battalion performed garrison duty at Corinth, Mississippi until the Confederates evacuated the town at the end of the month.

Afterwards, the battalion performed guard duty in northern Mississippi until the unit became part of the 6th Missouri Infantry on August 26.

After seeing action at the Battle of Plum Point Bend on May 10, the battery served as infantry and became part of the 6th Missouri on August 26.

[8] On the first day at Corinth (October 3), the 6th Missouri, as well as the rest of Green's brigade (less the artillery), began a charge against the Union line defended by Brigadier General Thomas A. Davies' division.

The Confederates met with heavy Union fire, and a cabin in the path of the 6th Missouri threw the regiment's ranks into confusion.

Another attempt at a Confederate charge was broken by a counterattack by the 2nd Iowa Infantry, the Iowans' attack hit the 6th Missouri the hardest.

A sergeant of the 6th Missouri described the charge by stating that "great gaps were thrown in their ranks [...] every instant death smote.

[14] The 6th Missouri suffered 223 casualties at Corinth, including Lieutenant Colonel Hedgpeth, who was severely wounded, and Major Vaughn, who was killed.

"[20] The charge of the Missourians broke through the Union line, capturing a crossroads and Champion Hill itself, both of which were strategic points on the field.

However, Union reinforcements commanded by Brigadier General Marcellus M. Crocker arrived, and the Missourians withdrew after more fighting.

[21] On May 17, the 6th Missouri was part of a Confederate force tasked with holding the crossing of the Big Black River.

[24] On May 22, the 6th Missouri strengthened the Confederate line near a point known as the Stockade Redan, helping to repulse Union attacks.

The consolidated regiment saw extensive action in the Atlanta campaign in 1864, including fighting at the Battle of Kennesaw Mountain on June 27.

[30] Thomas F. Harney, a former member of the 6th Infantry was later assigned to torpedo ordnance and arrested in the closing days of the war en route to bomb the White House with assistance from Cornelius Boyle and Mosby's Raiders.