The regiment was organized in Flint during the fall and winter of 1861–62 with men from the following counties: Shiawassee, Livingston, Genesee, Midland, Saginaw, Oakland, Sanilac, St. Clair, Lapeer, Jackson, Eaton, and Hillsdale.

It was also engaged at Boonville in July; was then ordered to Nashville and assigned to the 1st brigade and 1st division of Rosecrans' army.

On December 31 it guarded an ammunition train for the army, made a march of 54 miles (87 km) in 36 hours, and participated in the engagement at the Battle of Stones River.

On January 3, 1863, Companies A and D were attacked by a large force of Confederate guerrillas, but repulsed them, killing 15 and capturing at least that same number.

27 men of the 10th being near, they went forward and routed the enemy with heavy loss, capturing guns and horses and saving most of the convoy, which had been set alight.

It made a gallant advance over two sharp ridges but, being unsupported, was compelled to return to its earlier stand.

When Confederate General John Bell Hood attacked in defense of Atlanta, the 10th fought valiantly at Peachtree Creek.

The regiment was in the Grand Review at Washington D.C., moved to Louisville, Kentucky in June, and was mustered out on July 19.