Trikala borders the regional units of Karditsa to the south, Arta to the southwest, Ioannina to the west, Grevena to the north and Larissa to the east.

The northern part of Trikala is also mountainous and made up of forests and barren lands, the ranges here are Chasia and Antichasia.

The area of Trikala was relatively obscure in ancient Thessaly, as well as during the periods of Macedonian, Romans, and Byzantine rule.

Under the Ottomans, Trikala was known as "Tırhala" and became the seat of the Sanjak of Tirhala, encompassing most of Thessaly, until the late 18th century.

The region is directly linked to the rest of Europe through International Airport of Central Greece located in Nea Anchialos in a small distance from Trikala.