When the Civil War broke out in 1861, Cruft witnessed the First Battle of Bull Run as a civilian. This encouraged him to return to his native Indiana and raised the 31st Indiana Infantry; he was appointed its colonel on September 20, 1861. At the Battle of Fort Donelson, he commanded a brigade in Lew Wallace's division and was wounded during the fighting. He was again wounded, in the head, shoulder, and left thigh, at the Battle of Shiloh while leading his regiment in the Hornet's Nest. He was promoted to brigadier general of volunteers on July 16, 1862. He recovered and commanded a brigade at the Battle of Richmond, Kentucky, where he was again wounded. He commanded a brigade during the Battle of Perryville, but was not engaged in the fighting. He fought at Stones River and Chickamauga. At Chattanooga he commanded the 1st Division, IV Corps, and took part in the fight for Lookout Mountain. He led his division during the Atlanta Campaign and commanded a Provisional Division, composed of units from the Army of the Tennessee that could not rejoin William T. Sherman for the March to the Sea, at the Battle of Nashville. On March 7, 1865, President Abraham Lincoln nominated Cruft for appointment to the brevet grade of major general of volunteers, to rank from March 5, 1865, and the U.S. Senate confirmed the award on March 10, 1865. Cruft was mustered out on August 24, 1865.