Two bishop’s residences (that of Mytilene and Methymna), many large Early Christian basilicas (Basilica of St. Andreas, Afentelli, Chalinadou, Ispilometopon, Tsezmedon, Argalon etc.), countless settlements, scattered all over the island, cities (Mytilene, Molyvos, Eressos, Kalloni etc.) are evidence that life goes on on the island during the Early (325-64 AD) and Middle (542 AD) Byzantine era. During this time the island is subjected to a series of invasions (Slav, Avar, Saracen). During this time the island is also used as a place of exile for eminent personalities of the Byzantine (Couropalatis Leontas etc.). Large castles (the Castle of Mytilene, Avgerinou (Molyvos), Aghion Theodoron (Antissa), Eressos, Koraka (Kleious) and smaller fortresses (roughly thirty on the island) which are reinforced by watch-towers protect the population which take refuge inside their walls.

In 1087 AD Dzachas, an emir in Smyrna (Izmir) conquers the island.

In 1204 (occupation of Constantinople by the Venetians) the island belongs to Baldwin, emperor of Constantinople.

In 1235 Nice controls the island.

In 1304 Roger de Flor sacks Lesbos.

In 1335 Domenico Cattaneo attacks the island but it is regained by the Emperor Andronicus in 1336.

During the Byzantine era Lesbos belonged to the Province of the Isles. Monasteries, the history of which can be traced to the depths of time, stand out among other buildings of the time (the Monasteries of Ipsilou, Limonos and Myrsini, Metochi Perivoli, Kato Tritos etc.) while others are but ruins (Monasteries of Mount Livanos in Pterounda, Kriokopou etc.).