Commercial smooth-hound sharks of the genus Mustelus are commonly landed and consumed in Mediterranean fisheries, raising concerns about potential human exposure to persistent contaminants. This study investigated the occurrence of organochlorine compounds (OCs), including hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and its metabolites, and polychlorinated biphenyls (PCBs), together with per- and polyfluoroalkyl substances (PFAS), in muscle and liver tissues of Mustelus mustelus and Mustelus punctulatus collected in the waters of the Egadi Archipelago (central Mediterranean Sea). OCs were detected in all analyzed samples, with total PCB concentrations reaching higher values in liver compared to muscle tissues, reflecting tissue-specific accumulation and detoxification processes. PFAS were detected in all analyzed muscle samples (1.10–58.5 ng/g w.w.), with PFOS, PFOA and PFNA generally below current European regulatory thresholds, although isolated exceedances were observed. Stable isotope analysis (δ¹³C and δ¹⁵N) highlighted differences in trophic ecology between the two species and suggested that feeding habitat and trophic position may influence contaminant exposure patterns, particularly in M. punctulatus. The human health risk assessment, conducted as a screening-level evaluation, indicated potential concern associated with PCB concentrations in liver tissue, while risks associated with muscle consumption were generally lower. Overall, the integration of contaminant analysis and stable isotopes provides insights into organismal exposure pathways and supports the use of smooth-hound sharks as sentinels of contaminant presence in Mediterranean coastal ecosystems.