The 21^st SOS traces its lineage to the 21^st Pursuit Squadron (Interceptor) which was constituted on 22 December 1939. The squadron saw combat in Southeast Asia, from November 1967-August 1973. It also airlifted personnel from Saigon, in April 1975 and airlifted US Marines in rescue of the SS Mayaquez, in May of 1975 before inactivating on 22 September 1975 at U-Tapao, Thailand. The squadron reactivated on 1 May 1988 at RAF Woodbridge, UK.

The 21^st deployed to Incirlik Air Base, Turkey, on 6 April 1991 as part of Provide Comfort. In 1998 an MH-53from the 21^st SOS flew out of San Vito, Italy in support of the Bosnian peacekeeping mission.

The 21^st SOS participated in a combat search and rescue mission for the pilot of a downed F-117A during the air campaign against Serbia and the forces of Yugoslavian President Slobodan Milosevic. President Clinton called the 352^nd SOG commander to give personal thanks. In 1993, the unit deployed to San Vito while supporting Operation Provide Promise, a humanitarian airlift that sustained thousands of sick and starving civilians trapped by Bosnia's civil war. Eventually, that tasking switched to Operation Deny Flight.

On August 30, 1995, during the first day of Operation Deliberate Force, Serbian ground forces shot down a French Mirage, capturing its injured pilot and WSO. Unaware the airmen were prisoners, the unit flew nightly missions into Bosnia, hoping to locate and rescue the men. The unit also ferried troops into Sarajevo and Tuzla and played a key role in Bosnia's 1996 elections by flying 54 U.S. delegates throughout the war-scarred country.

The 21^st SOS  worked in a variety of theaters, such as evacuating civilians during African coup attempts or supporting Operations Southern and Northern Watch in Saudi Arabia and Turkey. It also rushed troops to Dubrovnik, Croatia, when an Air Force CT-43 carrying Commerce Secretary Ron Brown crashed into a mountain.

In early 1997 the unit departed for areas around Zaire to support Joint Task Force Guardian Retrieval. Pave Lows operated from Hoedspruit, South Africa where they were deployed in support of Operation Atlas Response, a multi-national humanitarian relief mission helping displaced people in Mozambique that have been devastated by floods. During Operation Iraqi Freedom, the MH-53Ms from the 21^st SOS conducted missions over Iraq.