Marine ecosystems are undergoing profound transformations due to climate change, challenging both biodiversity conservation and the sustainable use of marine resources. To ensure long-term effectiveness, marine spatial planning (MSP) must become ‘climate-smart’: it should preserve ecological functions and biodiversity under future conditions while ensuring the continued viability of the blue economy. Here, we identify climate refugia and climate hotspots across the Mediterranean Sea and assess the climate resilience of three alternative MSP zoning scenarios developed within the MSP4Biodiversity project of the National Biodiversity Future Centre. These scenarios (“SlowPace”, “Nature@Work”, “BlueDevelopment”) propose different zoning of marine uses in Italian waters, reflecting distinct policy priorities. Using a 3D climate velocity based on temperature analogues across the entire water column (comparing the periods 2006–2030 and 2031–2055), we mapped areas of environmental stability (potential climate refugia) and zones of intense change (climate hotspots). We then evaluated the extent to which each zoning scenario aligns with stable areas and avoids high-velocity or no-analogue zones. Our results reveal high exposure to climate change across all three pilot areas—Northern Adriatic, Northern Tyrrhenian, and Strait of Sicily—with the Northern Adriatic showing the highest rate of change. None of the scenarios sufficiently safeguards areas of future stability or strategically places climate-sensitive uses (e.g., fisheries, aquaculture, tourism). However, the conservation-oriented “Nature@Work” scenario demonstrates the highest potential for supporting biodiversity resilience and long-term adaptation. This analysis provides a framework for integrating climate adaptation into MSP by highlighting spatial mismatches between future climatically stable areas and current or projected marine uses. Our findings underscore the urgency of future-proofing marine spatial plans to support both ecological integrity and socio-economic goals in a rapidly changing ocean.