Environmental conservation is currently one of the main objectives of marine management. It is agreed that effective management requires evaluating the tradeoffs between protection and economic costs for negatively impacted maritime activities. For these reasons, integrated approaches combining ecological and socio-economic aspects are needed to achieve nature conservation and sustainability targets. Here, we present an approach to identify cost-effective priority marine areas for protection through a Systematic Conservation Planning method, adopting the Basque Country as case study (SE Bay of Biscay). Eight protection scenarios were defined, targeting a combination of protection features: benthic habitats, biological value of cetaceans, birds, macroalgae, and macroinvertebrates, potential provision of ecosystem services, and habitat sensitivity to human activities. In turn, the total fishing pressure produced by artisanal fisheries was adopted as a measure of the socio-economic costs of protection (assuming, for this research, that fishing would be banned in the protected areas). The results indicated that existing marine protected areas (MPAs) were very close to achieving prescribed protection targets, while these targets could be achieved by increasing the size of the existing MPAs. Higher costs were associated with the declaration of areas that were targeting a larger number of protection features. Nevertheless, cost/effectiveness was higher in these cases, with the environmental benefits outweighing a comparatively smaller increase in cost. However, the most cost-effective scenarios were those that included the extension of already existing MPAs. The method implemented can assist managers and decision makers in identifying conservation gaps and ecosystem components that require special attention. In addition, the approach can be used to develop management strategies that may be adopted under different protection scenarios. Thus, the approach proposed here could be used to inform ecosystem-based marine spatial planning.