Human-induced biodiversity loss has been accelerating since the industrial revolution. The climate change impacts will severely alter the biodiversity and biogeographical patterns at all scales, leading to biotic homogenization. Due to underfunding, a climate smart, conservation-prioritization scheme is needed to optimize species protection. Spatial phylogenetics enable the identification of endemism centers and provide valuable insights regarding the eco-evolutionary and conservation value, as well as the biogeographical origin of a given area. Many studies exist regarding the conservation prioritization of mainland areas, yet none has assessed how climate change might alter the biodiversity and biogeographical patterns of an island biodiversity hotspot. Thus, we conducted a phylogenetically informed, conservation prioritization study dealing with the effects of climate change on Crete’s plant diversity and biogeographical patterns. Using several macroecological analyses, we identified the current and future endemism centers and assessed the impact of climate change on the biogeographical patterns in Crete. The highlands of Cretan mountains have served as both diversity cradles and museums, due to their stable climate and high topographical heterogeneity, providing important ecosystem services. Historical processes seem to have driven diversification and endemic species distribution in Crete. Due to the changing climate and the subsequent biotic homogenization, Crete’s unique bioregionalization, which strongly reminiscent the spatial configuration of the Pliocene/Pleistocene Cretan paleo-islands, will drastically change. The emergence of the ‘Anthropocene’ era calls for the prioritization of biodiversity-rich areas, serving as mixed-endemism centers, with high overlaps among protected areas and climatic refugia.