During the precocious Byzantine period, Thessaly constituted the administrative department of Eastern Illyrikoy (4th-6th century) and afterwards the subject of Greece. It is the season of the expansion of Christianity , that rooted fast in the region of the current prefecture of Trikala, as it is testified by the existence of the bishopric of Trikki already from the 4th century.

From the moment that the new religion becomes the official religion of the empire, the construction of Christian churches also begins, and their presence in the region testifies the eminent early Christian pulpit that can be seen reconstructed in the church of Dormition of the Mother of God in Kalabaka, as well as the ruins of an early Christian temple that were found on the hill of the Prophet Ilias in Trikala. These are the first monuments that prove the transition from Later Antiquity to the Middle Times in the region.

The names of Gomfoys and Trikki, that are reported by Prokopios among the cities that Ioustinianos fortified again during the 6th century, arrive to us as an echo of another development when the countryside depopulates and the urban centers decline, while they accept the successive raids of tribes from the north: Goths in 396, Huns in 447, slavs in 527 and later, Saracen in 976, Bulgarians in 1025 and Normen in 1081 A.D. 

Since the 10th century, the flat region of the current prefecture of Trikala has been administered to the Subject of Thessaloniki while the mountainous region of Pindos to the Subject of Nikopoleos. During  the same period the name of Vlachs makes its appearance, Latin speaking people of the mountainous Thessaly and more specifically Pindos, with a dominant  presence in the history of the region, to the point that a department of Thessaly was named Great Vllachia from the 12th century. 

From the 10th century up to today, the Metropolis Stagon exists that resided in the city Stagon, the current Kalabaka (Aiginio of Antiquity). For the first time we encounter the name ‘Stagoi ‘ in the scripts of Leon the VI (9th-10th century) and we also know that Vassilios the II’ had visited the fortress of the city after the end of the Bulgarian war (beginnings of 11th century).

The name Stagoi, according to the wanderer Poykebil, is an alteration of the phrase ‘’to the saints’’ (probably meaning the rocks, because of the existing abbeys)-Stagious-Stagoys. Ioannis Bogiatzidis supports that the word emanates from the word Sitagogos- Stagos (threshing floor), while the archeologist-historian I. Giannopoylos attributes it to the Slavic word Stagia (booth, dent of a rock).

The name “Kalabaka”, begins to be used from the ages of Sultan Bagiazit the II’, after the Turkish conquest of Thessaly (1393-1394) and emanates as some say from the word “Kalebak” (beautiful fortress).

During the empire of Manoyil Komninos, the city of Stagon and its region was governed by the Serbians.

In 1204, the Franks conquer Istanbul and extend slowly towards whole Greece and the prefecture of Trikala passes to the sovereignty of the Greek Despotate of Epirus of Michail Aggeloy Komninoy Duke, who granted to his illegitimate son, Ioannis Aggelos Komninos Duke the control of Thessaly, that was named Great Vllachia.

Ioannis Aggelos is reported in a time note of 1788, which is written in the code 793 of the Monastery St. Panteleimon, St. Orous, as the founder of the monastery of Megalon Pylon, in the north of Pyli.

Pyli (Palia Porta) is built between Itamos and Koziakas, at the base that links Epirus with Thessaly and is separated by the river Portaikos from the new settlement of Porta Panagia, where the Byzantine city <<Megalai Pylai>> or Megali Porta was founded. The name “Pyli”(entrance) testifies how important was the location, as an entry to Epirus.

The Catalans upset and savagely plunder the Prefecture of Trikala in 1309-1311 , a time during which the administration of the region was in the hands of the Byzantine nobles Stefas and Michail Gabriilopoylos, with titles as lord of west Thessaly, Despot of Northern Thessaly, but formally the region was governed by the Despotate of Epirus.

The unreasonable taxation and the hard conditions that the Gabriilopoyloi imposed to the population, led to their removal and in 1333 W. Thessaly was governed again bythe Byzantine empire with Andronicus  III’ Palaiologos.

However, this peaceful period for the region will be very short, because after 1318, a lot of invaders covet the region of Trikala, mainly the Albanians, while in the interior a lot of civilian conflicts contributed to the siege of Thesssaly by the Serbians with the Souvereign Stefanos Doysan. He announced Grigorio Preloympio as governor of the region, with Trikala as the base, which previously was invaded and occupied without resistance.  

After the death of Grigorios Preloympios, the stepbrother of Stefanos Doysan, Simeon Oyresis undertakes the continuation of the Serbian power in Thessaly. Around 1370, Simeon Oyresis dies and leaves the throne to Ioannis Oyresis, who since 1359-60 had already been proclaimed co-emperor, at the age of 10.

Ioannis Oyresis Palaiologos, who is the last descendant of the Serb souvereigns, resorts after 1372 and before June 1373 to the Meteora to the Abbey of Metamorphosis, where he became a monk with the name Ioasaf.

As a secular sovereign, he publishes two “definitions-commands” in November 1372 in favor of the “first” hermitage of Stagon, Nile. Copies of these, are saved in a united leaf of paper in the Abbey of Metamorphosis and in particular are displayed in the Museum. In his personal hand-book-vademecum-vellum, that is located in the National Library of Athens, in the interior of the book his name exists holographly.

During the era of the Serbians the region of Trikala flourishes on a big intellectual level. The Serbian sovereignty in the region will interrupt the arrival of Turks in 1395.