Trikala is served by train on the line from Palaiofarsalos (on the Athens–Thessaloniki mainline) to Kalambaka. This makes it possible to arrive from Athens or Thessaloniki by rail with a change at Palaiofarsalos, though journey times are long. The more practical option for most visitors is by bus (KTEL) from Athens (about 4.5 hours) or Thessaloniki (about 3 hours). Larissa is about an hour by bus.
By car, Trikala lies on the E92 road that crosses central Greece. From Ioannina it's about 1.5 hours east through the Pindus mountains. Kalambaka and Meteora are 25 kilometres to the northwest, less than 30 minutes by bus or car.