The Rhodope Region is geographically connected to Thrace. It borders Bulgaria (Kardzhali Province) to the north, Xanthi Region to the west, Evros Region to the east and the Thracian Sea to the south, and has a coastline of approximately 58 km. The northern part of the region encompasses the eastern part of the Rhodope Mountains, from which it takes its name.

With the annexation of Western Thrace to Greece (1920), the problem of administrative assimilation also arose. Finally, by a legislative decree of 21 November 1923, Thrace was divided into two prefectures, Rhodope and Evros; the former included the territory of the later Xanthi Prefecture.

Rhodope was established as a prefecture in 1930, when the former Thrace Prefecture was divided into Rhodope and Evros Prefectures. In 1944, Xanthi Prefecture was formed from the western part of the Rhodope Prefecture. Since the 1990s, Rhodope has cooperated with Evros in the Rhodope-Evros Superprefecture.

As part of the 2011 Kallikratis government reform, the prefecture was transformed into a territorial unit within the region of East Macedonia and Thrace, without any changes to its borders.