Greene returned in 1861 to serve in the American Civil War. Although a Democrat, he was a strong abolitionist and at the beginning of the Civil War became colonel of the 14th Massachusetts Infantry, afterward the 1st Massachusetts Heavy Artillery. In 1862, while stationed with his regiment in Fairfax, Virginia he was recalled and assigned by General George McClellan to the command of an artillery brigade in Geneneral Amiel Weeks Whipple's division. He resigned his commission in October 1862 to continue his travels and writings.