The current regions were established in July 1986 (the presidential decree officially establishing them was signed in 1987), by decision of the interior minister, Menios Koutsogiorgas, as second-level administrative entities, complementing the prefectures (Law 1622/1986).

As part of a decentralization process inspired by Interior Minister Alekos Papadopoulos, they were accorded more powers in the 1997 Kapodistrias reform of local and regional government.

They were transformed into fully separate entities by the 2010 Kallikratis Plan (Law 3852/2010), which entered into effect on 1 January 2011.

In the 2011 changes, the government-appointed general secretary (γενικός γραμματέας) was replaced with a popularly elected regional governor (περιφερειάρχης) and a regional council (περιφερειακό συμβούλιο) with five-year terms.

Bordering the region of Central Macedonia there is one autonomous region, Mount Athos (Agion Oros, or "Holy Mountain"), an autonomous monastic community under Greek sovereignty.