The geography of the regional unit of Kilkis is characterized by the wide and flat Axios river valley in the westcentral part, and mountain ranges on its western and northeastern edges.

The mountain range in the west, on the border with Pella regional unit, is Mount Paiko (highest peak 1,650 m or 5,413 ft).

The border with Serres regional unit to the northeast is formed by the lower Kroussia range (highest peak 1,179 m or 3,868 ft).

They left their homeland in the South Caucasus for Kilkis and other parts of Greek Macedonia, as well as southern Russia and Georgia, between 1919 and 1921, that is, between the main Greece-Turkey population exchange and Russia's cession of the Kars region back to Turkey as part of the Treaty of Brest Litovsk.

The A1 motorway (E75, Skopje - Polykastro - Thessaloniki - Athens) runs through the regional unit from north to south.