According to mythology, when the Gods defeated the Giants the Giants, fled, and some of them sought refuge on the island of Kos. They were Koios, Phoebas and Kinnos, after whom the island was named -according to students of Mythology. According to tradition, king Triopas was the ruler of Kares, and he led them to the eastern coast of Kos where they built the town of Tiopo, on the current location of Agios Fokas. The successor of king Triopas was Meropas, who ruled the island which he named "Meropida" and the inhabitants "Meropes". Legend claims that Meropes built the first ancient city on the island, which they named after their king's daughter, Astipalaia. Triopas the 3rd was succeeded by his son Evdaimon whose successor was Eurypilos, the husband of Kletia and father of the future king of Kos, Halkonas, who built the fountain of Vourina. Another tradition claims that after Hercules performed his twelve feats, he was obliged by Euristheus to perform others, of less significance. One of his new tasks was to free princess Esione, daughter of Laomedon, king of Troas, who was tied to a rock so as to be eaten by a sea monster. Hercules saved her, but Laomedon did not pay him. Upset, Hercules destroyed Troas and returned home with six ships full of treasures. On his way home, a storm sank five of the ships, while, from the sixth ship, only Hercules and a few of his men managed to survive, seeking refuge on Kos's cape Gourniatis. They met a shepherd called Andagoras, there who was famous for his strength. The men asked the shepherd for a sheep, as they were starving, and he asked to fight Hercules, in return. The fight lasted many hours, and turning into a battle, when the people of Kos decided to help Andagoras. Hercules then hid in the house of a woman from Thrace, wearing her clothes. Eurypilos heard the news and ordered the arrest of Hercules. Then, the hero went to a mountainous area in Pili, which was named Fixa/Pixa (from fugitive). The locals helped Hercules fight Eurypilos. In the battle, Hercules captured Eurypilos's daughter, Chalkiope, whom he later married as he left for Folegandros. From Hercules union to Chalkiope, Thessalos was born. He later became king of Nissiros and Leros. Thessalos had sons who were captains of the ships participating in the Trojan War, representing Kos, Kalymnos, Nissiros, Karpathos and Kassos.

During the Mycenaean Era, Kos was a crowded and overdeveloped island which participated in the Trojan War. In the 7th and 6th century BC, Kos was a member of the Six Dorian Cities along with Alikarnassos, Knidos, Lindos, Ialissos and Kamiros. After the end of the Persian Wars, Kos became a member of the Athenian Alliance. In the 4th century BC, the island became one of the most significant naval and commercial units, while it also thrived in the Hellenistic Era. In the 2nd century BC, the island was conquered by the Romans, but it flourished once again in the Byzantine years. In the 11th century, Kos suffered pirate raids as well as, the rule of the people of Genova and Venice, while it came under the command of the Knights of Rhodes, in 1315. In 1522, the island was occupied by the Turks, who prosecuted, punished and massacred the locals. During the Greek Revolution in 1821, Kos supported the Greek side. On 6 June, 1821, the Turks hung 92 leading citizens by the plane tree of Hippokrates, while another 26 people were hung at Kako Prinari, as an example of the punishment awaiting those who helped the Greek cause. In 1912, Kos came under the Italian command, while in 1948 it was united with Greece, along with the rest of the Dodecanese islands.