The earliest traces of habitation in Despotiko date back to the Early Cycladic Period (3rd millennium BC). In two places on the south side of the island, in Livadi and Zoumbaria, they were excavated at the end of the 19th century. by Christos Tsountas two Early Cycladic cemeteries with box-shaped tombs containing vessels, marble utensils, jewelry and figurines on display at the National Archaeological Museum. More tombs came to light in Zoumbaria in 1959 by N. Zafeiropoulos. Traces of residential installations have recently been identified at the Chiromylos and Zoumbaria sites.
The next phase of habitation on the island dates back to the Geometric Age (9th-8th century BC), when in the place Mantra, in the northeastern peninsula of the island, an installation of a cult character is established. In the same place in the archaic years the city of Paros establishes the great sanctuary of Apollo that operates until the Hellenistic years. During the Roman period the sanctuary ceased to function and its buildings are reused for habitation until the early Byzantine period (6th century BC). After centuries of abandonment, the place was re-inhabited in the late Byzantine period, until the 17th century. The fate of the Despotic was inextricably linked to that near Antiparos. Thus, it passed under the jurisdiction of the Venetians, first to the House of Sanudes in 1207 and then to other Venetian lords until 1537, when Antiparos and the other islands of the Cyclades passed to the Ottomans. In fact, many architectural members from the buildings of the sanctuary have been transferred and reused in the Venetian castle of Antiparos. The settlement of the late Byzantine years was founded on the ancient buildings and is identified with the castle that is distinguished in maps and engravings of the 15th, 16th and 17th century. In 1657, as an act of revenge for the surrender of the pirate Daniel to the Turks, the settlement in Despotiko was looted by French pirates and since then the island has been permanently abandoned. In 1756 it came under the ownership of George Bao of Mykonos and the Despot of Parian Petros Mavrogenis.
For the last two hundred years, shepherds from Antipari have installed animal herds on the island, the largest of which is in the place of Mantra, on the ancient remains of the sanctuary of Apollo, using building materials from the buildings of the sanctuary. However, the number and importance of the archeological sites have now made the Despotic archaeological site of absolute protection. At the same time it is protected by the forest service due to the special Cycladic vegetation, which consists of cedars, snakes and creeping cypresses, making it an island of special natural beauty.