What would become Pease Air Force Base started as the 300-acre (120 ha) Portsmouth Municipal Airport in the 1930s. With the onset of World War II, improvements to the airport were announced in December 1941. The airport was closed to civilian traffic effective August 1942, as part of defense measures along the east coast. Civil Air Patrol usage started in February 1944, and in August the airport was leased to the U.S. Navy, who already had a nearby presence at Portsmouth Naval Shipyard.

The U.S. Air Force assumed control of the airport in 1951, when the installation was selected for development as a Strategic Air Command (SAC) base. Purchase of additional land for expansion of the base started in 1952 and was completed in 1956. Ground breaking for the new SAC facilities took place in 1954, and the first B-47 Stratojet bombers arrived in 1956. Renamed Portsmouth Air Force Base, the installation formally opened on 30 June 1956. On 7 September 1957, it was renamed Pease Air Force Base in honor of New Hampshire native Captain Harl Pease Jr., USAAC, who was posthumously awarded the Medal of Honor for heroism during World War II.

Pease AFB was the home of the 100th Bombardment Wing and from 1958 onward the 509th Bombardment Wing, the latter arriving from Walker AFB, New Mexico, as successor to the famed 509th Composite Group of World War II that had executed the atomic bombings of Hiroshima and Nagasaki and had transitioned to the B-47 and KC-97 in the mid-1950s. Their mission was strategic warfare in the event of war. From 1956 until its closure in 1991, Pease Air Force Base maintained a combat-ready force for long-range bombardment and nuclear strikes. B-47 Stratojet, B-52 Stratofortress, and FB-111 Aardvark bomber aircraft, as well as KC-97 Stratofreighter and KC-135 Stratotanker air refueling aircraft and C-97 Stratofreighter, C-124 Globemaster and C-130 Hercules cargo aircraft, were all based at Pease AFB at varying times. In 1961 and 1962, the base received consideration as a potential site for Minuteman missile deployments.

The 100th Bombardment Wing was converted in June 1966 to a strategic reconnaissance wing and transferred to Davis-Monthan AFB, Arizona. This left the 509th Bombardment Wing as the principal host wing for Pease AFB. The 509th was phased down for inactivation in 1965, but, cognizant of the historical significance of the 509th in SAC, the wing converted to the B-52D and KC-135A and was redesignated as the 509th Bombardment Wing, Heavy, in 1966. From 1 April to 1 October 1968 and from 26 March to 20 September 1969, more than one-half of the wing was deployed in Southeast Asia. The 509th supported SAC combat and contingency operations in Southeast Asia with KC–135A aircraft and crews from 1966 to 1975, and with B–52D aircraft and crews from 1966 to 1970. By 1 December 1969, the wing had transferred all its B-52D aircraft to other SAC units in preparation for transition to the General Dynamics FB-111A. Redesignated as the 509th Bombardment Wing, Medium, the 509th had no bomber aircraft from November 1969 until 1970, but continued KC-135 refueling and alert operations and performed FB-111 ground training. The wing resumed flying training with the FB-111 in December 1970 and assumed FB–111 alert commitments from 1 July 1971 until September 1990. During this time, the 509th won the SAC Bombing and Navigation Competition and the Fairchild Trophy in 1979, 1981, 1982, and 1983, and the Sanders Trophy for best air refueling unit in 1982.

In 1966, the New Hampshire Air National Guard relocated the 157th Military Airlift Group (157 MAG) from the deactivating Grenier AFB in nearby Manchester, New Hampshire, to Pease AFB. Operating the C-97 Stratofreighter, the group transitioned to the C-124 Globemaster in 1968 and to the C-130 Hercules in 1971. The mission of the group was changed in 1975 when it was designated as the 157th Air Refueling Group (157 ARG) and transitioned to the KC-135A in 1975. The 157th later transitioned to the KC-135E in 1984, the KC-135R in 1993, and to the KC-46A in 2019.

Pease AFB served as a base conducting summer field training for U.S. Air Force Reserve Officer Training Corps (AFROTC) cadets during the 1960s and '70s.

Air Force Base closure

In December 1988, Pease AFB was one of 86 military installations to be closed as part of the Secretary of Defense's Base Realignment and Closure process. In 1989, 3,461 active-duty military, 741 civil service workers and 347 non-appropriated fund employees were employed at Pease AFB. Of the total active duty personnel, 49 were assigned to the Air National Guard. It is estimated that the base created a total of 2,466 secondary jobs within the local communities. Military personnel began leaving the base in June 1990, and Pease AFB officially closed on 31 March 1991.

The 509th BW transferred its FB-111 aircraft to Tactical Air Command and its KC-135s to other SAC units.