UNESCO’s World Heritage Centre has set ten criteria for assessing Outstanding Universal Values (OUVs) for the inscription of properties on the World Heritage List. Recognising the growing challenge for heritage conservation and the need for professionals to work within systemic, holistic, and integrated frameworks in managing cultural heritage and using biodiversity as an OUV, this paper investigates how the intangible and tangible cultural and natural heritage of the Region of East Macedonia and Thrace, Greece is interconnected over the course of centuries. We review the evolution of the existing legislative framework to protect archaeological treasures and local flora and fauna and document the richness of ongoing ecological and biological processes in the region for strengthening the arguments for an integrated protection and management system. Locating the archaeological sites and monuments in protected natural zones and areas of exceptional beauty with the use of the open code QGIS programme and focusing on their description and analysis, the present research recommends their interlinked management under the leadership of a Joint Destination Management Organisation.