During its domination in Kos (1337-1522) the Battalion of the Knights of Saint John fortified and upgraded the Byzantine network of fortresses on the island. In those times Kos was an independent unit to which Kalymnos and Leros belonged to. The command of the Knights was carried out by few commanding officers but they offered sufficient protection from the attacks of the pirates and the Muslim empire. According to the Knights records which can be found in Malta today,
the commanding officer’s responsibility was to ensure the safety of the residents, the enforcement of justice, secure ownership of land and also protect the residents from arbitrariness of military power. One of the most important tasks of the military was the preservation of the castles and fortresses. Today we can still see eleven different fortresses on the island. The most well-known being the Castle of Old Pyli, and the Castle of Andimahia.

Since the 15th century and especially after taking over Constantinoupoli in 1453, the Ottomans tried to take over from the Knights in the Dodecanesse. Initially they asked for a tribute tax, after the refusal by the Knights to pay, they began systematic attacks on the island, forcing the residents to leave many times and seek refuge in the castles. After the take over of Rhodes by the Ottomans in 1522, Kos along with other islands of the Dodecanesse pass into the Sultans hands. The economy of the island depends on agriculture and commerce
from the harbour. The Castle Neratzia is a safe commercial stop for ships.

The first mention of the early Christian period in Kos is connected to the visit of the disciple Paul which is mentioned in the book of Paul. This was recorded in the minutes of the first Ecumenical Synod of Nice in 325 and was signed by the bishop of Kos Melifron.
The big earthquake in 469AD signaled the change in the structure of architecture from the Roman times to Christian times. However, the next earthquake was very strong in 554AD and destroyed the city of Kos.This made it difficult for the city to get back to its former glory. Life continued along the same lines till the Arabic Invasion in the middle of the 7th century. Until the 7th century Kos remained a member of the Province of the Islanders whose capital Kos - Early Christian Byzantine Periodwas Rhodes. From the middle of the 7th century Kos belonged to the Kibireoton or Aegean or Samos. In the second half of the 11th century we are informed that Nikiforos Melissinos, husband of Evdokia who was the sister of the emperor Alex the first Komninou resided in Kos where he owned a lot of land. At the same time a large number of royal related people came to Kos like Christodoulou who founded the monastery of Theotokou in Old Pyli. Christodoulou exchanged the land in Kos with land in Patmos where he founded the monastery of St John Theologou. From the 11th century till the beginning of the 14th century Kos had many administrative changes up until the occupation by the Knights of Ioannites.