Abstract <p>The pollution of aquatic ecosystems by pharmaceutical residues and heavy metals is an increasing environmental and public-health concern in coastal regions. This study quantified selected pharmaceuticals residues and heavy metals in surface water and sediments from the Khniss drain and from Monastir marine area, and assessed their ecological and human-health risksWe measured nine pharmaceuticals (including azithromycin and climbazole, caffeine, etc..) and seven heavy metals (Pb, Cd, Ni, Cu, Fe, Zn, Mn) in wastewater effluents, drain water, marine water, and sediments. Ecological risk was assessed using Risk Quotients (RQ) for pharmaceutical compounds in surface waters and the Risk Index (RI) for heavy metals in sediments. Human health risk assessment included the evaluation of non-carcinogenic risk, expressed as the Hazard Index (HI), and carcinogenic risk (CRI) associated with heavy metals in sediments for both adults and children. For pharmaceutical in surface waters, potential human health risks were evaluated using RQ. Azithromycin and climbazole posed high ecological risks to aquatic organisms. In sediments, lead (Pb) and cadmium (Cd) concentrations were elevated and were the main contributors to the sedimentary RI. Correlation analyses showed strong positive relationships between concentrations of several pharmaceuticals and heavy metals, suggesting common pollution sources. Non-carcinogenic risks (HI) were below concern thresholds for both adults and children. However, chromium shows the highest CRI values, often surpassing the 10^–4 threshold for both children and adults, indicating a high carcinogenic risk This study provides the first comprehensive environmental baseline for the Khniss drain and nearby marine ecosystem, identifies azithromycin, climbazole, Pb and Cd as primary environmental concerns. Findings support the urgent need for improved wastewater management, coastal protection measures, and continued monitoring in the southern Mediterranean.</p>