According to the myth, Lassithi was the birthplace of Zeus. The history of Lassithi is strongly associated with the history of the rest of Crete. Lassithi Plateau was the center of the Minoan civilization and it has been inhabited since the Neolithic times. The cave of Trapeza is one of the most important sources that confirm the existence of human activity there.
Many towns were established in Minoan times, such as Vassiliki, Lato, Zakros, and Gournia and there are traces of the development of ceramic art, metalwork, and architecture. From about 1450 BC, there is a decline of the Minoan civilization with the arrival of the Dorians, who marked a new culture and built new cities.
During the Classical and Hellenistic times, the cities of Lassithi were destroyed by civil wars and were later captured by the Romans in 66 BC. In 395 AD, Crete island became part of the Byzantine Empire. The region of Lassithi is particularly rich in Byzantine monuments and characteristic frescoes. In the 13th century BC, the region was surrendered to the Venetians who fortified the entire island. To ensure their control, the Venetians fortified Sitia, Ierapetra and other towns, among them the famous Spinalonga. Crete was strongly influenced by the Venetian culture in language, traditions, and political morals. Despite the resistance of the Cretans against the Venetians, their influence led to the flourishing of letters and art.
After the Venetian occupation, the island is surrendered to the Turks from 1669 to 1898. During the last years of Turkish rule, the settlement of Agios Nikolaos was built, named after the Byzantine temple that lays there. The Cretans fought strongly against the Turks and in 1898 the island gained its autonomy and became officially part of Greece in 1913.