According to mythology, the first inhabitant of Siros was Coeranus, who arrived here on a dolphin, after his ship sank near Paronaxia. Coeranus sought refuge in a cave, currently known as "Coeranion Andron". In the Odyssey, Homer mentioned the island of Siriin, reigned over by Ktissios Ormenides.

Siros, first inhabitant in the Neolithic Era, has been one of the centres of development of the Cycladean civilization. The Phoenicians lived on the south-western port of the island, followed by the Ionians in 1,000 BC. The latter founded two cities, one of which lay on the current location of Ermoupoli. The great philosopher Pherecydes, Pittacus's student and Pythagoras's teacher, lived here in the 6th century BC. During the Persian Wars, Siros supported Athens, while later it became a member of the Athenian Alliance. The island was occupied by the Macedonians, the Ptolemese of Egypt and the Romans, while in the Byzantine Era, it was a member of the Scheme of the Aegean Sea. In the 13th century, Siros was occupied by the Venetians, who built the Medieval town of Ano Siros and converted the locals to Catholicism. The people of Siros remain Catholics to this day. In 1537, the island was conquered by the Turks by whom it was granted special privileges, not granted to any other Cycladean island. In 1821, Siros was under the protection of the French. In 1822, the island was stormed by the people of Psara and merchants from Chios, who came here because they were prosecuted by the Turks. They built Ermoupoli, which was declared the capital of the prefecture of the Cyclades in 1833, after the arrival in Greece of Othon.