Lieutenant Mason was still at Fort Vancouver when news arrived in April 1861 of the outbreak of the Civil War and the bombardment of Fort Sumter in Charleston, South Carolina. After the departure of Edward O. C. Ord, Mason assumed the role of post commander at Fort Vancouver on May 7, 1861 and remained in that position until June 11, when relieved following the arrival of Capt. Henry K. Black of the 9th U.S. Infantry.. Later in May, he was promoted to a captaincy in the 11th U.S. Infantry. In October of that year, he was appointed as the colonel of the three-years' 4th Ohio Infantry. He joined 4th OVI in western Virginia, where they served during the fall and winter under command of Maj. Gen. James Shields. In 1862, Mason's regiment participated in the Peninsula Campaign of Maj. Gen. George B. McClellan, where they guarded Harrison's Landing. He was involved in the Maryland Campaign and the Battle of Antietam. Late in the year, he commanded a brigade in Maj. Gen. John Sedgwick's II Corps' "Right Grand Division" and fought at the Battle of Fredericksburg. He was cited for gallantry in both of those actions and brevetted. On November 29, 1862, he was promoted to the rank of brigadier general of U. S. Volunteers. His health, never robust following the two yellow fever bouts, again failed him and Mason asked for and received administrative duty. In April 1863, Mason was assigned to muster and recruit duty, first in Ohio, and for the last two years of the war in California as an Adjutant General, and finally in the new state of Nevada. He was promoted to Major of the 17th U.S. Infantry in the Regular Army in 1864. Mason was responsible for John Hunt Morgan and his raiders imprisoned in Columbus, OH at the time that seven escaped. From March 7, 1865 - July 21, 1865 he was commander of the District of Arizona under the Department of the Pacific. In the omnibus promotions at the end of the Civil War in 1865, he was brevetted through the Regular Army grades to that of brigadier general.
Postbellum career
Mason remained in the U.S. Army following the war. He subsequently performed garrison duty in a number of outposts on Western frontier in the 1870s and the 1880s. He was transferred to the 15th U.S. Infantry in March 1869. He was promoted to lieutenant colonel of the 4th U.S. Infantry in 1873 and to colonel of the 9th U.S. Infantry in 1883. His stations included the states and territories of Texas, New Mexico, Wyoming, Washington, D.C., Ohio, and Arizona. Mason was a cousin of President James A. Garfield’s wife Lucretia and during the Garfield administration was Deputy Governor of the Soldiers Home at Washington. He was married twice, first to Anna Worrell Judkins and then to Cornelia Wilson. Mason was active in veterans affairs, particularly in the Military Order of the Loyal Legion of the United States. He retired in 1888 as the colonel of the 9th U.S. Infantry at Fort Whipple, Arizona, and took up residence in Washington, D.C., where he died at home on November 29, 1897, from general paralysis brought about from a stroke. He was buried with full military honors in Section 1, Grave 541, of Arlington National Cemetery. One of his sons, Captain John S. Mason, Jr., perished at the army post at the Pine Ridge Indian Reservation from exposure in the line of duty, and is also buried at Arlington National Cemetery. Another son, Charles, also served in the Army.