Some of the first exercises of the new command took place in 1952. Operation Ancient Wall was a series of military manoeuvers involving ground small unit tactical training, land-based tactical air support, and carrier-based air support.

The drawdown of the British Mediterranean Fleet, the military difficulties of the politically-decided command structure, and the withdrawal of the French from the military command structure forced a rearrangement of the command arrangements in the southern region. Allied Forces Mediterranean was disbanded on 5 June 1967, and all forces in the south and the Mediterranean assigned to AFSOUTH.

The Commander-in-Chief of Allied Forces Southern Europe has always been a United States Navy Admiral, based at Naples, who also holds the national appointment of Commander-in-Chief United States Naval Forces Europe.

From 1967 the overall shape of AFSOUTH did not significantly change until the command was renamed in 2004. There were five principal subordinate commands (PSCs).The number rose to six when Greece was taking part in the military structure; Greece withdrew from the NATO military structure after the Turkish military action in Cyprus in 1974, and after some behind the scenes negotiating by NATO officials, returned in October 1980.

Two land commands, Allied Land Forces Southern Europe and Allied Land Forces Southeastern Europe, were tasked to defend Italy and Turkey respectively. Each was directly responsible to Commander-in-Chief, AFSOUTH, and supported by a tactical air force, 5th Allied Tactical Air Force in Italy and 6th Allied Tactical Air Force in Turkey. The two allied tactical air forces were under an overall air command, Allied Air Forces Southern Europe, headquartered at Naples in Italy under a United States Air Force officer, ComAirSouth, responsible himself to CinCAFSOUTH.

Due to political considerations, command of the naval forces in the region was split. Allied Naval Forces Southern Europe, at Naples, operated most of the NATO allies naval forces in the Mediterranean under an Italian admiral. But due to the U.S. desire to retain control of their nuclear-armed naval forces, the United States Sixth Fleet reported directly to CinCAFSOUTH, supported by a separate headquarters named Naval Striking and Support Forces Southern Europe or STRIKFORSOUTH. The sixth command was an Allied command responsible for the land defence of Greece, named Allied Land Forces South-Central Europe or LANDSOUTHCENT. Below these PSCs were smaller headquarters such as Maritime Air Forces, Mediterranean, at Sigonella, Sicily, responsible for coordination of the aerial anti-submarine effort, Submarine Forces, South, and the Naval On-Call Force Mediterranean, a multinational escort squadron activated at intervals.

From 1992 AFSOUTH was heavily involved in NATO operations in the Balkans, initially with NATO seaborne enforcement of a UN arms embargo, Operation 'Maritime Monitor,' which began in July 1992. This operation was fused with a similar Western European Union effort and thus became Operation Sharp Guard from July 1993. AFSOUTH also directed activities such as Operation Deny Flight from AIRSOUTH headquarters in Italy. Commander-in-Chief AFSOUTH directed the NATO peacekeeping missions in Bosnia & Herzegovina, IFOR and SFOR, from December 1995.

The reorganisation of AFSOUTH as JFC Naples in 2004 was a part of NATO's transformation, initiated by the Prague summit of 2002, aimed at adapting the allied military structure to the operational challenges of coalition warfare, to face the emerging threats in the new millennium. The new NATO Command Structure is leaner, more flexible, and focused on conducting a much wider range of missions.