During the American Civil War, Griffin served first as a captain in the 2nd New Hampshire Infantry from June 1, 1861 to October 31 of that year. He served as lieutenant colonel of the 6th New Hampshire Infantry from November 28, 1861 until he became colonel on April 22, 1862. Griffin led his regiment in First Brigade, Second Division, Ninth Army Corps. He led the regiment in the Second Battle of Bull Run, the Battle of Antietam and the Battle of Fredericksburg. Griffin led first brigade second division briefly during the winter of 1862-1863.
