After the fallen of Istamboul from the Crusaders of Fourth Crusade (1204) and the creation of Latin Empire of Bosporus, the Dandolos granted the islands in his nephew, Mark Sanoudo. In this way, the Duchy of Naxos or Archipelago had been established. Thira became the seat for one of the four Latin bishoprics of Duchy and, with Thirassia, was granted as barony to Iakov Varotsi. Until 1296 the island was managed by five generations of Varotsi family, which they made use of the pompous title "Despotai of islands Santorini and Thirassia".

Thira tooks the name "Santorini" from a small church of Saint Irine (Santa Irini). There is a believes that the name came from the church in Perissa or from others that came from a church in Rivas of Thirassia.

In the years of Frankish rule (1207 - 1579), Santorini followed the fate and the history of remainder islands of Duchy of Naxos. At this years was expelled the family Varotsi (1335) and the Barony was blamed in the Duchy. Under the hegemony of Sanoudes, the island knew big bloom with the growth of the cotton cultivation. During the period of power of Duke Jacob of Krispon dynasty (1397 - 1418) Jacob studied particularly the volcano while the later concession of Santorini in the Duke of Crete Dominico Pisani, brought new latin bishop under the protection of Venice and was thus strengthened the agriculture with particular growth of culture of cotton and viticulture.

Follows finally, the annexation of island, with the remainder Duchy, in Venice (1487). In entire the duration of Frankish rule, the islands suffered so much from the piratical raids, what from the competitions aamong the local latin dynaties or between the Duke and the Sultan. The same period, the coexistence of two christian communities of - catholic and orthodoxe - above in the island, often created their frictions between them, instigated by the religious leadership of both communities.

Turkish conquest (1579 - 1821) contributed in the repression of piracy and in the growth of trade. The traders created narrow relations with the big harbours (Alexandria, Istamboul, Odessa) the Eastern Mediterranean, where they founded also important colonies. Their economic independence from these activities is now visible in old mansions that are saved still in the villages of Santorini.