The Aegean Sea stands as a unique Mediterranean ecoregion with intricate geomorphological attributes and diverse habitats. This article delves into the sea’s rich biodiversity and the challenges of managing its resources sustainably. The Aegean’s complex structure encompasses shallow shelves, deep basins, and a multitude of habitats, mirrored by a high species richness. However, cumulative impacts from human activities pose significant threats to marine biodiversity. Assessments of conservation status are limited, primarily due to data constraints. We argue for the need for an ecosystem-based management (EBM) approach as the cornerstone for integrated marine management in the Aegean, building upon previous research in the region. The framework of Drivers-Activities-Pressures-State-Impacts (to human Welfare)-Response (Measures) (DAPSI(W)R(M)) facilitates the understanding of interactions between human activities, ecosystem changes, and societal impacts. At the same time, a Social-Ecological System framework can inform on possible synergies and/or tradeoffs of decision-making for a more inclusive governance structure hence advancing the EBM approach. We underscore the need to transition from sectoral management to EBM and marine spatial planning, guided by a comprehensive governance structure, using tools and concepts of Social-Ecological systems for an advanced EBM. We propose an array of concrete actions spanning from enhanced scientific research and stakeholder involvement to adaptive governance structures and addressing global change impacts. This holistic approach, emphasizing interdependence and balance, aims to pave the way for the Aegean Sea’s preservation and prosperity in the face of mounting challenges.