The European eel (Anguilla anguilla) is a critically endangered species. The impact of environmental contamination on this species has been highlighted as contributing to the decline in recruitment. The Mar Menor hypersaline coastal lagoon (SE Spain) is one of the most productive fisheries of European eel in Europe, making it a critical habitat for species conservation. The present study aimed to provide an initial overview of the impact of organic chemical contaminants on the European eel and the potential sublethal effects of chemical pollution on pre-migrating eels in this hypersaline habitat. We investigated muscle bioaccumulation of main persistent and hazardous organic contaminants (including some current-use pesticides) and genotoxicity, neurotoxicity, and xenobiotic detoxification system responses. The findings show that lagoon eels were exposed to high levels of legacy organochlorine contaminants, recently banned pesticides (chlorpyrifos), and some emerging chemicals. Some individuals surpassed the maximum levels of CBs authorized by the European Commission for human consumption. In this species, residuals of chlorpyrifos, pendimethalin, and chlorthal dimethyl have been reported for the first time. This field study provides relevant data to stock management and human health consumption and provides the first biomarker responses in European eel under permanent hypersaline conditions. Furthermore, the high frequency of micronuclei in peripheral erythrocytes of lagoon eels indicates sublethal genotoxic effects on the organism. Overall, the European eels growing and maturing in the Mar Menor lagoon are exposed to toxic and carcinogenic chemicals. The lack of seafood safety regulations for human consumption for some legacy chemicals that were measured in high concentrations in our study requires special action. Further biomonitoring and research are recommended to protect the animal, public, and environmental health.