Climate- and land-use change stand as primary threats to terrestrial biodiversity. Yet, their synergistic impacts on species distributions remain poorly understood. To address this knowledge gap, we conducted the first-ever comprehensive species distribution analysis on an entire regional endemism centre within an eastern Mediterranean country, incorporating dynamic land-use/land-cover change data together with climate change scenarios. Specifically, we apply species distribution modelling and spatial data analysis techniques to compare the individual and synergistic effects of these environmental drivers on the endemic vascular flora of Peloponnese, focusing on potential range contractions, altitudinal shifts, and habitat fragmentation levels. Moreover, we identify fine-scale present and potential future endemism hotspots within our study area, incorporating taxonomic and phylogenetic information. Overall, we aim to enhance our current understanding of endemism patterns and contribute to the development of future-proof conservation strategies for safeguarding Greece's endangered endemic flora. The integration of land-use change projections with climate change yielded less severe impacts compared to the effects anticipated when considering climatic variables alone. Most taxa are expected to undergo significant range declines and nearly half might experience increased habitat fragmentation, due to the synergistic effects of climate- and land-use change. We identified endemism hotspots, which are concentrated in or along the main Peloponnesian mountain massifs. However, our predictions indicate that areas presently recognized as endemism hotspots will undergo a concerning area decline, across all future scenarios considered in this study. Our findings highlight the importance of including dynamic land-use variables alongside climatic predictors when projecting species distributions under global change. Moreover, we showed that endemism hotspots are not static and considering their potential geographic shifts is paramount to delineate effective forward-looking conservation strategies.