According to mythology, when Danae bore Perseus to Zeus, her father shut her inside a box with the baby and threw them into the sea. The box reached Serifos and a fisherman gave them refuge. Politheukis, king of Serifos, fell in love with Danae but she did not reciprocate his feelings and was supported by her son in this. Politheykis sent Perseus to kill Medussa, hoping that he would die. Perseus returned with her head at the sight of which Politheykis and everything else on the island were petrified.

Serifos was first inhabited by the Aeolians and had adopted democracy in the 7th century BC. During the Persian Wars, it took the part of the Greeks. It was subjugated to Athenians, Macedonians and Ptolemies respectively and was taken by the Romans in 146 BC. During the Franks rule, it was governed by many Venetian rulers and its mines enjoyed great acme. The Turkish domination marked Serifos, since it was completely at the mercy of pirates. In May of 1821, the flag of revolution was raised on the island, and Serifos was liberated with the rest of the Cyclades.