As a colonial regiment operating in the American wilderness, the regiment was quick to incorporate changes in tactical doctrine based on conditions encountered in fighting Native Americans in King Philip's War and other conflicts, requiring each militiaman to own a modern flintlock musket prior to 1675.

At the onset of the American Revolutionary War, the Massachusetts Provincial Congress, meeting as a shadow government, ordered the activation of the 1st Middlesex County Regiment on 19 April 1775.

It was mustered into federal service at Camp Meigs, Readville, Massachusetts, in July 1864 for 100 days service and served with the VIII Corps in the Middle Military Division (Baltimore and vicinity) before being mustered out on 16 November 1864 at Readville and resumed state militia status as the Massachusetts Volunteer Militia.

[5] The 5th Massachusetts was mustered into federal service on 25 June 1916 at Framingham for duty on the Mexican Border while stationed at El Paso, Texas.

The 5th Massachusetts was redesignated on 11 February 1918 as the 3rd Pioneer Infantry Regiment, and served in the U.S. First Army sector in France.

Conducted annual summer training most years at Fort Devens, 1921–34; and at the Massachusetts Military Reservation (Camp Edwards) at Falmouth, 1935–39.

As part of a piecemeal transfer of the Americal Division, the 182nd was deployed to combat in the Battle of Guadalcanal on 12 November 1942, where the regiment's 3rd Battalion participated in an operation to capture the Japanese defensive works atop the Sea Horse, a prominent terrain feature on the island.

Maintaining contact with elements of other U.S. Army regiments in the assault, the 3rd Battalion began its ascent, and by 30 December was in action against Japanese forces atop the Sea Horse.

In 2008, the remains of Lt. Raymond S. Woods of the 182nd Infantry Regiment, who was killed in action on 30 December 1942 in fighting atop the Sea Horse Ridge, were located and transferred to JPAC.

[9] In 2008, the squadron completed a 15-month tour of active duty in Kosovo supporting the NATO efforts there as part of Task Force Patriot.

One notable contribution of the Task Force was the collection of school supplies and textbooks for children in remote areas of the country through its civil affairs program.

An online article by the Massachusetts Army National Guard, dated 3 August 2009, stated that the unit would soon revert to an infantry configuration.

In March 2011, the 1st Battalion 182nd Infantry mobilized for service in Afghanistan in support of Operation Enduring Freedom.

Delta company 2nd platoon was inserted into Assadabad Afghanistan at FOB WRIGHT in June 2011 and manned remotely positioned observation post Nevada upon a ridge line 8 kilometers from the Pakistan border over seeing the Sar Kani village and the Kunar valley.

They received many distinguished decorations to include the Purple Heart, the ARCOM; they conducted more than 75 combat missions in which they were either a gunner, driver or dismounted personnel, the NATO award was awarded for service in relation to ISAF operations, the over seas service ribbon (OSR), the global war on terrorism service medal (GWOTSM), Afghanistan campaign medal with 1st campaign star, certain members of the platoon were awarded the Combat Infantry Badge for direct participation in ground combat action for having been personally present and under hostile enemy fire in Afghanistan, Pech Valley, Kunar province while leaving Cop Honaker-Miracle the patrol was ambushed with IED explosion dividing the element in half they relied on their training and prevailed with no casualties, on 17 Aug 2011 while serving with PRT Kunar in direct support of operation enduring freedom, the NAVY achievement medal was awarded to the national guard soldiers that were attached with the Navy element At the end of March 2012, having been relieved by the 143rd Infantry, the 182nd Infantry was released from active duty, having completed its tour in Afghanistan.

Together, A, B, C, D and HHC secured critical facilities in Jordan, Kuwait, Saudi Arabia, Qatar, and the United Arab Emirates.