- For ancient Greeks Thrace was the place from where Voreas and God Aris were taking the warpath. In mythology it is mentioned as the birthplace of Orpheus and other mythical composers.
- Our knowledge on the prehistoric Thrace is limited; there are findings of the Paleolithic era, while for the Neolithic era we have information only in north Thrace. On the territory of the Prefecture, close to Diomidia, Melissa, Lefki, Chrisa, as well as Thermes where the grand bas-relief depicting Mithras is, scientists discovered ancient settlements. There is significant information on the life and culture of Thracians in Homer's writings.
- During the 7th century the colony of Avdira was established, a city of development and wealth. The Greek civilization begins in Avdira and enters the life of Thracians. People from Klazomenes of Asia Minor establish a colony for 50 years. Inhabitants from the Ionic city of Teo settle in Avdira in an effort to avoid the Persian troops. Finally they settle down permanently. During these years the Persians visit Avdira. The city continues its development until 5th century. It becomes a member of the 1st Athenian Alliance. Later it was taken over by Filippos the Second and was annexed to the Macedonian reign. After many years it was taken over by the Romans and its decadence began.
- In ancient times we also have human presence in the mountainous regions where scientists discovered the Macedonian tomb and several castles such as the one of Kaliva, which was built by Filippos the 2nd.
- During Roman and Byzantine times Topiros city which was located close to Nestos river, was connecting Macedonia with Thrace. In Xanthi prefecture apart from Topiros, the cities of Avdira-Polistilo, Anastasioupoli and Xanthia-Xanthi were also eparchies.
- Xanthia-Xanthi has been known since 879 A.D. from its bishop Georgios. The findings show that probably in ancient times at its place there were settlements. From13th up to 14th century it is the most important city of the region.
Three monasteries stand on its hills: Pammegiston Taxiarxon, Panagia Archaggeliotisa and Panagia Kalamou. All of them were built on the ruins of older Byzantine or post Byzantine buildings. In the two latter monasteries there were manuscripts of 12th century proving the existence of the older monasteries. The manuscripts were taken by the Bulgarians during their invasion in the period of 1913-1919.
- The Ottoman occupation of Xanthi and in southwest Thrace starts by the end of 14th century. Close to Egnatia Road a new regional center named Genisea is established. Xanthis is also called Isketje and is inhabited by Greek Christians.
The development and evolution of region are connected with tobacco cultivation which first started in the region of Thessaloniki in 17th century and afterwards it began to develop in Xanthi. In 18th century Genisea and Xanthi became famous worldwide because of tobacco production. In 19th century Porto Lagos is the export center of all products arriving from the rich agricultural valley of Genisea. During 19th century Genisea, the administrative and commercial center of the region and Xanthi, the center of Greek Christians are two rival cities. In 1829 two strong earthquakes destroyed the city of Xanthi which was quickly reconstructed, while in 1870 a massive fire burns Genisea and so the administrative and commercial center is transferred to Xanthi. In 1912 it was conquered by Bulgarians and in 1913 (13th of July) it was liberated by Greeks. But in 1913 (28th of July), after the convention of Bucharest it is given back to Bulgarians.
By the end of the First World War in 4/10/1919 it is again liberated by the Greeks.
In 1941 during the Second World War it was conquered by the Germans who give it again to Bulgarians. It was finally liberated in 1944 and in 1945 it officially joined to the Greek State.