European seas are experiencing rapid development. The anthropogenic demand for marine resources and space exerts the need for novel concepts for sustainable resource exploitation and smart space allocation. Multi-Use (MU) is an emerging concept to overcome spatial claims and support Blue Growth, however its actual potentials and current status of implementation in different sea basins is to a large extent unexplored. An analytical framework using a mixed method approach is proposed for the identification and analysis of MU potentialities in eight EU countries of the Euro-Mediterranean sea basin. The paper addresses opportunities and challenges of ten existing and potential MU combinations driven by three maritime sectors: tourism, renewable energy and Oil & Gas industry. Opportunities and challenges for MU development were presented in terms of drivers, added values, barriers and impacts. Results show that highest potential for MU development are related to tourism-driven MU combinations (e.g. pescatourism), but also emerging MU potentials exist related to Floating Offshore Wind energy and aquaculture (Gulf of Lion) and the re-use of Oil & Gas decommissioned platforms (Northern-Central Adriatic Sea). Findings were discussed for their geospatial distribution and their policy, socio-economic, technical and environmental boundary conditions. Recommendations on actions to foster MU development in the Euro-Mediterranean sea space are provided.