The island of Sant'Antioco was settled at least from the 5th millennium BC (the so-called culture of San Michele of Ozieri), which was based mainly on fishing and agriculture.

In the 8th century BC the Phoenicians founded a new settlement, with the name of Sulky (Punic: SLKY)[2] or Solki,[citation needed] of which a tophet (children) necropolis has been excavated.

It was repeatedly attacked by the Saracens starting from the early 8th century, and gradually abandoned by the inhabitants who fled to the more protected inner area; the island mainly remained important as the end of pilgrimages devoted to St. Antiochus.

In January–May 1793 the island was occupied by French troops under admiral Laurent Jean François Truguet, and the citizens freed from ecclesiastical taxes.

The last attack by North African pirates occurred in 1815;[4] the same year in which the relics of the patron saint were brought back to the cathedral.