The regiment recruited its members starting on July 15, 1862, from the 4th Congressional District which included the Michigan counties of Barry, Ionia, Montcalm, Kent, Ottawa, Muskegon, Oceana, Newaygo, Mecosta, Mason, Manistee, Grand Traverse, Leelanau, Manitou, Osceola, Emmet, Mackinac, Delta, and Cheboygan.

The regiment left its quarters at Ionia, Michigan, on 12 September in command of Colonel Stevens, 1,008 strong, under orders to report at Cincinnati.

A beautiful silk flag was provided by the ladies of Ionia and delivered to the 21st Michigan Volunteer Infantry Regiment on 6 September 1862, at that city.

The 21st Michigan left Nashville on 26 December 1862, with the army, in command of Lieutenant Colonel McCreery, and was engaged at Lavergne on the 27th, and at Stewart's creek on the 29th.

It participated with Sill's brigade of Sheridan's division in the five days' Battle of Stone's River, sustaining a loss of 17 killed, 85 wounded, including Captain Leonard O. Fitzgerald, mortally, and 37 missing.

The 21st was in the hottest of the fight, behaved with great courage, never yielding except when overcome by immense odds, but after a brave but fruitless effort against a perfect torrent of the enemy was compelled to give way.

On November 1, 1864, the 21st, then in command of Colonel Bishop, was at Dalton, Ga., where it received orders to march to Kingston and join the 14th army corps, and on arriving there was assigned to the 2d brigade, 1st division, when it started for Atlanta, and on the march assisted in tearing up the railroad track and destroying everything in its rear, reaching that point on the 15th, and on the following day after the destruction of that place, moved with General Sherman's army towards Milledgeville, arriving there on the 22d, and then took up a line of march in the direction of Augusta, and on reaching within about forty miles of that point, turned directly south towards Savannah, and arrived at the works in front of that place on 10 December, and there relieved a part of the 20th army corps, which held a portion of the works on the south side of the canal, being the most exposed position on the whole line.

There the men being obliged to stay in the trenches, without tents and lightly clad, few of them having blankets, suffered extremely from cold, and also from hunger, as their rations were short.

The regiment continued in that position until the 15th, when it moved back north of the canal, and remained there until the evacuation of Savannah on the 21st, and then encamped about three-fourths of a mile from the city.

The regiment remained at Savannah, refitting, reclothing the men, and getting ready for the campaign through the Carolinas, until 20 January, 1865 following, when in command of Captain A. C. Prince, it marched up along the Savannah river to Sister's Ferry, where it lay until 5 February, then crossed into South Carolina, still continuing the movement in the vicinity of the river until nearly opposite Columbia, when a direction was taken towards that point, and on arriving there turned to the left, crossed the Black and Saluda rivers, and struck the railroad at Winnsboro, where it assisted in destroying the track as far north as Blackstock Station; then changing the direction eastward, crossed the Great and Little Pedee rivers about eight miles north of Cheraw, then crossed the Wateree at Rocky Mountain, on pontoons made from wagon boxes covered with tent flies and canvas, the high water having carried away the pontoon bridge.

From Richmond the march was continued to Washington, D. C., where the regiment participated in the review of General Sherman's army on 24 May, and on 8 January was mustered out of service, when it proceeded to Michigan, arriving at Detroit on the 13th, and on the 22d was paid off and disbanded.