This study provides a comprehensive evaluation of contamination levels in the Romanian Black Sea within the framework of the Marine Strategy Framework Directive (MSFD). Over the course of five oceanographic expeditions between 2020 and 2022, data were gathered from 70 stations in transitional, coastal, shelf, and offshore waters of the Black Sea. Analyses were conducted on water, sediment, and biota samples for key contaminants: heavy metals (HMs), polycyclic aromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs) such as organochlorinated pesticides (OCPs) and polychlorinated biphenyls (PCBs). The assessment identified contamination hotspots near riverine inputs, urban runoff, harbor activities, and industrial discharges. Offshore waters also showed measurable pollutant levels, likely from diffuse sources and atmospheric deposition. The key findings reveal the widespread contamination of HMs, PAHs, and POPs across the Romanian Black Sea, with concentrations in certain areas exceeding acceptable environmental thresholds, highlighting ongoing challenges for regional pollution management. PAHs were prevalent in both nearshore and offshore regions, while OCPs and PCBs were detected across various matrices, with significant concentrations observed in water and biota samples. The study emphasizes the importance of integrated assessments within the MSFD framework, suggesting that future evaluations should complement the “one out-all out” (OOAO) approach with multi-metric tools, to enhance the robustness of pollution status reporting. Despite improvements in some areas, contamination remains a critical challenge, requiring strengthened regulations, improved waste management, and increased regional cooperation to mitigate the ongoing risks to marine ecosystems. The findings provide valuable data for the upcoming national MSFD assessment cycle (2018–2023) and highlight the need for sustained monitoring and coordinated efforts to ensure long-term marine sustainability.