In 1861, the 27th New York Infantry elected Slocum as their colonel. On July 21, 1861, they were involved in the First Battle of Manassas, in which Slocum was wounded. He was on sick leave until September 1861. In August, Slocum was promoted to Brigadier General, in the service of the defenses of Washington, from September 1861 to March 1862. He participated in the Peninsula Campaign, the Siege of Yorktown, the Battle of Gaines Mill, the Battle of Glendale, and the Battle of Malvern Hill. In the Maryland campaign, Slocum served at South Mountain, and at Antietam. After Antietam, Slocum was given command of the XII Corps, and with them, he participated in all the major engagements of the Army of the Potomac from Fredericksburg to Gettysburg. After Gettysburg, Slocum was to be send west to serve under Joseph Hooker. He protested this move by submitting his resignation to Lincoln, who orchestrated a compromise. In September, Slocum was sent to command During the summer of 1864, he commanded the District of Vicksburg and the XVII Corps of the Department of the Tennessee. Slocum continued in positions of high responsibility for the rest of the war, eventually rising to command of the Army of Georgia under Major General William T. Sherman in the campaign of the Carolinas near the end of the war.