The southeastern part belongs to the Thessalian Plain. The forested Pindus mountain range dominates the western part. The northern part of Trikala is also mountainous and made up of forests and barren lands, the ranges here are Chasia and Antichasia. Its major river is the Pineios, flowing to the south and east.
Its climate is mainly of Mediterranean character, with hot summers and cold winters, along with temperate climate conditions by the mountains.
Trikala was created as a prefecture (Greek: Νομός Τρικάλων) in 1882. As a part of the 2011 Kallikratis government reform, the regional unit Trikala was created out of the former prefecture Trikala. The prefecture had the same territory as the present regional unit. At the same time, the municipalities were reorganised, according to the table below.