The Minnesota 5th Infantry Regiment was mustered in 19 December 1861 at Fort Snelling and was fully organized 20 March 1862, at which time three Companies were detached for garrison duty at Forts Ridgely, Ripley and Abercrombie. While posted at the Sioux Agency on the Yellow Medicine River, and while investigating a report of an Indian massacre in the Lower Sioux Agency area, a Company was ambushed at the river about 2 miles from the Agency at which 23 men soldiers were killed, 5 wounded, and their commander Capitan Marsh drowned while attempting to cross the river.

Elements of the Regiment were later at Oxford and Georgetown, Mississippi, Germantown Tennessee, Corinth, Mississippi, and were eventually assigned to the 2nd Brigade, 1st Division, Army of the Mississippi. The Regiment was at Farmington, Clear Creek, until August, and then relocated to Tuscumbia, Alabama.

The 2nd Brigade moved towards Corinth, with the Regiment acting as rear-guard and participating in the Battle of Iuka. On 3 October it held the crossing at Tuscumbia Creek near Corinth and the following day drove the enemy back, retaking the Batteries the enemy had previously captured. Division Commander General Stanley said the Regiment saved the day at Corinth.

The Regiment then supported several campaigns and expeditions through central Mississippi and western Tennessee until 1 February 1863, when it rejoined its command near Memphis. Then it took part in the advance on Vicksburg in the spring where it was in the assault on Vicksburg 24 May. In June it traveled up the Yazoo River, and was involved in skirmishes at Satartia, Mechanicsburg and Richmond; was then assigned to guard duty on the river until the fall of Vicksburg when it joined in pursuit of Johnston's Army.

It was encamped at the Big Black River and participated in various expeditions during the fall; was in camp at La Grange from November, until late in January 1864, and was then ordered back to Big Black River.

  Regiment members reenlisted almost to a man 12 February, becoming a part of the 2nd Brigade, 1st Division, 16th Corps. The Regiment joined the Red River Expedition in March, participated in the assault and capture of Fort De Russy, Mississippi; was in a reconnaissance to Henderson's hill; took part in the engagement at Campti, when the Confederates were routed, acted as the rear-guard for the supply train when Banks was defeated at Sabine Crossroads, formed part of the Corps which met Taylor's pursuing columns at Pleasant Hill, and repulsed repeated assaults until Banks' broken lines could be reformed and fortunes reversed in their favor.

 During the time the Federals were beleaguered by the Rebel Taylor Army, the Regiment was an integral part of the rear-guard in the retrograde movement, being engaged by the enemy every day until Alexandria was reached. The Regiment was in the engagement at Mansura, and with its Corps defeated Taylor's troops at Bayou de Glaize, Louisiana. It reached Vicksburg, Mississippi on 24 May and was in combat at Lake Chicot, Arkansas in June.

 The veterans were furloughed home in July, and those who had not reenlisted were in the battle of Tupelo. The Regiment returned to Holly Springs on 17 August, was in an engagement near Abbeville on the 23rd, then participated in the Arkansas and Missouri campaigns during the fall of the year, and the Battle of Nashville in December, where its Division captured two redoubts with their batteries, gunners and hundreds of prisoners. The following day it lost 106 of its number, but won the position, although its colors were shot down four times.

 Winter quarters were at Eastport, Mississippi from 10 January until 6 February 1865. In the spring they participated in the siege of Mobile, and in the assault on Fort Blakely, Alabama prior to the surrender. It was at Demopolis, Alabama during the summer and was mustered out at Fort Snelling 6 September 1865.

 The Regiment's total strength during service, including recruits was 1,163. Loss by death, 248, transfer, 28; resigned 26; discharged 434; captured 6; deserted and missing 51; mustered out 370.

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