Climate change poses a great challenge for biodiversity conservation. Several studies exist regarding climate change’s impacts on European plants, yet none has investigated how climate change will affect the extinction risk of the entire endemic flora of an island biodiversity hotspot, with intense human disturbance. Our aim is to assess climate change’s impacts on the biodiversity patterns of the endemic plants of Crete (S Aegean) and provide a case-study upon which a climate-smart conservation planning strategy might be set. We employed a variety of macroecological analyses and estimated the current and future biodiversity, conservation and extinction hotspots in Crete. We evaluated the effectiveness of climatic refugia and the Natura 2000 network of protected areas (PAs) for protecting the most vulnerable species and identified the taxa of conservation priority based on the Evolutionary Distinct and Globally Endangered (EDGE) index. The results revealed that high altitude areas of Cretan mountains constitute biodiversity hotspots and areas of high conservation and evolutionary value. Due to the “escalator to extinction” phenomenon, these areas are projected to become diversity “death-zones” and should thus be prioritised. Conservation efforts should be targeted at areas with overlaps among PAs and climatic refugia, characterised by high diversity and EDGE scores. This conservation-prioritisation planning will allow the preservation of evolutionary heritage, trait diversity and future ecosystem services for human well-being and acts as a pilot for similar regions worldwide.