In April 1861 Pierce enlisted in the Massachusetts state militia. He was first assigned to the defense of Fort Warren until he was appointed to succeed to the brigade command of General Benjamin Butler. In June 1861 in the first land battle in Virginia, Pierce was in command under General Butler; however, his advance was repulsed by the enemy and he was relieved of his command. He reentered the service to be elected colonel of the 29th Massachusetts Infantry. He lost his right arm at Nelson's Farm in the Battle of Glendale in June 1862. He rejoined his command in March 1863. His unit was ordered with the Ninth Corps to Cincinnati, Ohio, where he took charge of the new post at Paris, Kentucky. In May 1863 he was ordered to Vicksburg. Pierce arrived in the midst of the battle on June 14th. During the Fall of 1863, he led his men into Tennessee where they were involved in the battles of Blue Springs and Campbell's Station before they were ordered back to Virginia. Pierce stayed with his regiment until he was discharged in November 1864.