Identifying key sites of marine biodiversity value and implementing the required practical spatial management measures is critical for safeguarding marine biodiversity and maintaining essential ecological processes, especially in the face of accelerating global change and expanding ocean economies. Delineating Ecologically or Biologically Significant Marine Areas (EBSAs) has been catalytic in progressing toward this aim. However, the Benguela Current Large Marine Ecosystem (BCLME; comprising three developing countries: Angola, Namibia, and South Africa) is one of few places where practical action to secure biodiversity in EBSAs has followed their description. We aim to document the process of moving from biodiversity priority areas to implemented conservation actions, and distil broadly applicable emerging lessons. EBSAs in the BCLME were reviewed using a systematic conservation planning approach, supplemented with expert input. In this data- and knowledge-driven process, the boundaries and descriptions of existing EBSAs were refined, and gaps filled with new EBSAs. The status of 29 EBSAs was assessed by determining the ecological condition, ecosystem threat status, and ecosystem protection level of constituent ecosystem types. Also, current human uses and their respective impacts were systematically reviewed per EBSA. Management recommendations were proposed by dividing EBSAs into zones with associated multi-sector sea-use guidelines. Throughout the process, facilitated by a regional cooperation project, there was stakeholder engagement, and national, regional, and international review. BCLME States are currently implementing enhanced EBSA management in their respective marine spatial planning and marine protected area processes, noting that there are different but valid outcomes for securing marine biodiversity in each country. Further, the regional approach allowed for cross-border alignment of priorities and management between countries, as well as pooled expertise, technical support, and capacity development. Although full implementation is still underway, the lessons to date highlight some key factors required for a successful process that could guide similar initiatives elsewhere.