The 21st SQUADRON was established in Macedonia on 25th May 1918 with the 73rd and 111th Flights. On the 25th August 1919 it was disbanded but later reconstituted at Ciampino airfield during 1939 with the FIAT G-50 fighters and eventually with the MC 200. With these aircraft's the unit moved to the Capodichino airfield where it fought over Neapolitan and roman skies defending those cities. From 1942 to 1943 the 21st Squadron was moved to the Russian front, where it flew with honor.

After the armistice, it became an Aeronautica del Sud Unit operating the MC 202 and the RE 2001. When the second world war ended the 21st Squadron lived within the 51st Wing ranks flying the Spitfire, P-47, F-84G and F-86K on numerous airbases in northern Italy and finally at the Istrana airbase. During 1963 the 21st Squadron moved on to the F-104G and was transferred to the Cameri airbase, where it became part of the 53rd wing during 1967 as the “All Weather Fighter Interceptor Squadron”. In 1968 it reached the status of NATO tiger member, the allied squadrons’ prestigious association linked by the tiger emblem heraldry, that meets once a year during the exercise named “Tiger Meet”. In 1971, the first F-104G flew with the unit and from 1989 to 1996 the 21st Squadron operated with the F-104S ASA, flying over 82,000 hours on the “Starfighter”.

During 1996 it began the transition onto the Tornado ADV which then ended in 1997. The following year the 21st Squadron won the prestigious “Silver Tiger” trophy at Lechfeld’s Tiger Meet. From October 1998 to July 1999 the unit was temporarily deployed to Gioia del Colle airbase to participate in NATO operations “Deliberate Force” over Bosnia and with allied forces in Kosovo. Within this last operation the 21st Squadron flew numerous combat missions over Balkan skies to protect NATO air forces during air strikes over Serbia. On the 29th of July 1999, the unit moved to Gioia del Colle airbase becoming part of 36th Wing.
On the 1st of March 2001, the unit reached “Quadro” status, but on the 23rd of March 2006 the 21st Squadron was reactivated with the 387th and 388th Flights at Grazzanise airbase, flying the Agusta Bell AB-212CO helicopters. The new duty of the 21st Squadron is to ensure the aerial support for the Special Forces division, or Special Operational Forces divisions stationed abroad on foreign missions, as well as carrying out combat SAR operations. Thus leading to the immediate involvement in the ISAF mission in Afghanistan from April 2006. In February 2010, the Squadron reached 2000 flight hours in Afghanistan.

In 2022 they converted to the HH-101A Caesar Helicopter.