According to Greek mythology, Nissiros was formed during the battle between the Giants and the Gods. Neptune persecuted Polivotis the Giant who, terrified, crossed the Aegean Sea, seeking salvation. Neptune captured Polivotis near the islands of Kos. The god returned part of the island, Krikelos, with his trident and hit the Giant with it. Thus the island of Nissiros was formed, and Polivotis has been sending his sighs, via the volcano to earth ever since. Modern writers identify Neptune with Atlas carrying the Earth on his shoulders. They also claim that Nissiros is the centre of the earth. Neptune was worshipped in Nissiros as the creator and protector of the island, thus there is a temple dedicated to Neptune here, and the coins have his head on them. Other gods worshipped on the island were Hermes from Delos, Apollo from Nissiros, Melehios Zeus, Tihi and Dionysous.

The first inhabitants of Nissiros were the people of Karos, followed by the people of Kos, Thesalie and Rhodes. In the Persian Wars, Nissiros supported the Queen of Alikarnassos, while the island was also a member of the Athenean Alliance from which they dispatched quite early. Nissiros's autonomy lasted until 200 BC, when the island was offered to Rhodes, and Nissiros's history coincided with the history of the island of Helios. Nissiros suffered four violent Turkish attacks in 1457, 1471, 1480 and 1505. These attacks forced the locals to seek refuge in Rhodes and return to Nissiros after the establishment of the Turkish Occupation. Like all the Dodecanese islands, the Italian Rule in 1912 ended the Turkish Occupation. The language and the religion of the Italian ruler were established, forcing the locals to emigrate once again. The island of Nissiros was liberated after the end of World War II' and Nissiros was united with Greece on 7 March 1948, like the rest of the Dodecanese islands.