The battalion saw extensive combat during the Civil War, participating in twelve campaigns with the Army of the Potomac.

During the Peninsula Campaign, the 12th Infantry distinguished itself in its first combat action at the Battle of Gaines' Mill in June 1862, while sustaining fifty percent casualties.

The regiment also participated in such historic battles as Antietam, Fredericksburg, Chancellorsville, Gettysburg and six additional campaigns culminating with the Siege of Petersburg, Virginia, from late summer 1864 through April 1865 and the war's end.

In April 1869, having been ordered to the Presidio of San Francisco, California, the regiment entrained at Omaha, Nebraska, on the Union Pacific Railroad portion the not yet finished transcontinental railroad; rode to Corinne, Utah; detrained and marched to the Central Pacific railhead; and re-entrained to complete the journey to Sacramento, California.

[3] In the 1870s, the regiment took part in three campaigns of the Indian Wars; against the Modoc tribe in California during 1872–1873, against the Bannocks in the Northwest in 1878, and against the Sioux at Pine Ridge, South Dakota from 1890–91.

There, the regiment participated in three campaigns (Malolos, Tarlac, and Luzon 1899) of what was to be known as the Philippine–American War and then served as garrison troops, not returning to the United States until 1912.

Deployed along the Mexican border, the regiment repulsed Villista harassing attacks during the Battle of Nogales in 1915.

On 17 December 1917 the 12th Infantry was assigned to the 8th Division at Camp Fremont, California, but was not sent overseas in World War I.

After its arrival, the regiment remained in strict quarantine until after its convoy had sailed, and was not released until 11 November, the day the armistice ended the war.

The regiment temporarily transferred on 7 May 1926 to Camp Anthony Wayne, Pennsylvania, and participated in the Sesquicentennial Exposition in Philadelphia until 11 December 1926.

The 3rd Battalion established the first Civilian Conservation Corps (CCC) camp in the United States near Edinburg, Virginia, on 17 April 1933.

The primary ROTC "feeder" school for new Reserve lieutenants for the regiment was Pennsylvania State College.

The 12th Infantry was awarded the Presidential Unit Citation for valor in action at Luxembourg during the Battle of the Bulge.

In 1956, the Division returned to the United States and was stationed at [[Fort Lewis (Washington) In 1957, the Army decided that in the era of battlefield atomic weapons, tactical infantry regiments were obsolete.

To reinforce NATO, the 1st Division was directed to begin Operation Long Trust whereby the individual battle groups were rotated on temporary duty to West Germany.

It was then ordered to proceed to Berlin overland through East Germany using the Helmstedt-Berlin autobahn to test the Warsaw Pact's willingness to allow NATO forces to continue to use it.

By the early 1990s, the Army draw-down and its expanding worldwide peace-keeping commitments led to a decision to scrap the unit replacement concept before it was fully implemented.

The 1st Battalion was inactivated at Fort Carson in September 1995, after returning from deployment to Guantanamo Bay as a part of Operation Sea Signal.

Much of their fighting was conducted in notoriously dense grape fields, which provided excellent concealment for insurgent forces.

During its time in the Pech Valley, the 2nd Battalion saw heavy fighting throughout their area of responsibility at the foothills of the Hindu Kush mountains.

In June 2010, Task Force 1-12 and Lethal Warrior (2-12), 4th BCT, 4 ID redeployed to Fort Carson, Colorado, after 12 months in Afghanistan.

In March 2012, 1st and 2nd Battalions, 12th Infantry Regiment, 4BCT, 4 ID, again deployed to Afghanistan in support of Operation Enduring Freedom.

A series of articles published by David Philipps in the Colorado Springs Gazette chronicles the 2nd Battalion of the 12th Infantry Regiment.