The Sixth was organized in August, 1862, under the President's second call for troops, six of the companies coming from Baltimore. Leaving that city on September 19, 1862, it proceeded to Williamsport, on the Upper Potomac, where it joined the Maryland Brigade. It left that brigade in March, 1863, and became a part of the Third Brigade, Second Division (Milroy's), Eighth Corps. This division retired before Lee's advance to Gettysburg, but not without some hard fighting at Winchester, Va., in which the Sixth was engaged; it then moved into Maryland, where it was subsequently assigned to the Third Corps, becoming the Third Division.

The regiment was in the Third Corps at Mine Run, in which affair it took a prominent part, being then in Keifer's (2d) Brigade, Carr's (3d) Division, Third Corps. The principal engagement of the Mine Run campaign occurred at Locust Grove, a fight which devolved almost wholly on Carr's Division, and largely on the Sixth Maryland. In March, 1864, the entire division was transferred to the Sixth Corps, the regiment becoming a part of the Second Brigade (Col. B. F. Smith's). Upon its transfer to the Sixth Corps, the division was placed under the command of General Ricketts. Colonel Howard resigned May 5, 1863, and was succeeded by Colonel Horn, who resigned in February, 1865.

The Sixth fought with signal gallantry in the battles of the Wilderness and Cold Harbor, its losses in the former action being unusually severe. On July 6, 1864, the division was ordered on transports at City Point, Va., and sailed for Baltimore to meet Early's invasion of Maryland. Owing to delay in transportation, the regiment did not arrive in time to participate in the battle of the Monocacy, but in time to cover the retreat of Ricketts's Division. General Ricketts was wounded at Cedar Creek, and was succeeded by General Seymour. The regiment did some good fighting in the Valley, and, also, in the final battles of the war. It was mustered out June 20, 1865.