Towards the end of the 6th century B.C. The Persians under their King Darius, had dominated the Greek cities in Asia Minor.  Kalymnos as well as Kos were forced to pay a heavy tribute to Darius and became satellite states of his empire.  Both islands however refused to take part in the Persian war against the rest of Greece which was still liberated. After the defeat of the Persians in 480 B.C. at the naval battle of Salamina and the total destruction of the Persian fleet at the Mykalis pass between the island of Samos and Asia Minor (479B.C.)

During the Peloponnesian war; 431 - 404 B.C. the Kalymnians allied with the Athenians.  During the war they were invaded by the Spartan admiral Astyocho, who did not however manage to install an oligarchic command faithful to Sparta and so Kalymnos soon returned to the Athenian alliance. Ιn 333 B.C. after the fall of Halicarnassus to Alexander the Great's generals (Ptolomeus, and Asantros) Kalymnos, like the surrounding islands, was delivered from the Halicarnassus domination.

From 220 to 215 B.C. Kalymnos is subject to Kos which together with Rhodes and Rome, took part in the war against Phillip the 5th of Macedonia.  (Not to be confused with FYROM or Skopje which has usurped the name in recent times.) Rome is the up and coming power of that age and takes full advantage of the disputes between Alexander the Great's successors to further extend its supremacy.

In 554 A.D. one of the most terrible earthquakes ever occurred.  The earth shook for 14 days and is well documented by the historian Agathias who happened to be in Kos at the time.  The frightening tremors and explosions made the earth subside and the sea rushed in and ravished the coastline taking with it people, buildings and anything else in its way. In 1306 A.D. kalymnos is conquered by the Knights of the Order of Saint John from Jerusalem.