Karpenisi is situated in the valley of the river Karpenisiotis (Καρπενησιώτης), a tributary of the Megdovas, in the southern part of the Pindus Mountains.

It is called Switzerland of Greece for the resemblance with the mountainous country and its beauty, atypical for a Mediterranean place.

The Greek spelling Καρπενήσι is influenced by folk etymology, the second combining form appearing to be νησί 'island' (pronounced [niˈsi]).

[8] During more recent times, the region took part in WWI and WWII, becoming the place where the armed National Resistance was initiated.

[8] Due to its altitude, Karpenisi has a temperate climate (Köppen: C), with abundant rainfall year round and much cooler temperatures.