At the end of the third century AD, the Roman Empire was divided in two by the Emperor Diocletian , and in 395, after the death of Theodosius, it was permanently divided into the Western Roman Empire and Eastern Roman Empire. The island of Kos , Greece as a whole, will become part of the Eastern Empire, it remained for eight centuries
The Roman Empire became Christian during the reign of Constantine the Great (306-337 AD) who founded the city of Constantinople on the site of the ancient city of Byzantium. In this booming Byzantine Empire, Kos became the seat of a bishopric and counted a population of 160 000 inhabitants.
In 469, the magnificent buildings of the Greco-Roman city and the Asclepieion were severely damaged by an earthquake, followed by another in 554.
From the beginning of the fifth century to the early seventh century, the island was attacked by barbarian hordes (Goths, Vandals, Bulgars, Avars, et cetera). In the second half of the seventh century, it was the Arabs who devastated the island.
Despite the looting and destruction caused by earthquakes, archaeological remains dating from the early Christian period are impressive. The most important monuments of the era were, no doubt, many great basilicas whose ruins have been discovered in many areas around the island of Kos. Most of them are decorated with impressive mosaics produced by local workshops renowned for their artistic quality. In addition, along the coast of the island (in the current locations of Kefalos , Kardamena and Mastihari ), large settlements were discovered, they included spacious buildings and streets. This prosperity ended with the Arab raids which forced most people to take refuge in the interior of the island.
From the beginning of the twelfth century, Kos was among the areas claimed by the Republic of Venice. In 1204, after the conquest of Constantinople by the Crusaders, Kos and other islands of the Dodecanese ceased to be part of the Byzantine Empire.