Immune system responses in fish are considered as suitable and sensitive biomarkers for monitoring aquatic pollution. However, a clear knowledge gap persists in the literture on the immunotoxic potential of engineered nanoparticles toward aquatic organisms such as fish. Employing major enzymatic- (glutathione reductase, GR; glutathione peroxidase, GPX; glutathione sulfo-transferase, GST; catalase, CAT) and thiol- (non-protein thiols, NP-SH; total glutathione, TGSH)-based defense biomarkers, this study assessed the response of phagocytes isolated from peritoneum (P-phagocytes), gill (G-phagocytes), head kidney (HK-phagocytes), and spleen (S-phagocytes) of European eel (Anguilla anguilla L.) to silica-coated magnetite particles (Fe3O4@SiO2/SiDTC, hereafter called IONP; size range: 82 ± 21 to 100 ± 30nm; 2.5mgL(-1)) alone and IONP and mercury (Hg; 50μgL(-1)) concomitant exposures. Responses of previous biomarkers were studied in P-phagocytes, G-phagocytes, HK-phagocytes, and S-phagocytes collected during 0, 2, 4, 8, 16, 24, 48, and 72h of exposures. Contingent to hour of exposure to IONP, Hg, and IONP + Hg GST, GPX, CAT, NP-SH, and TGSH exhibited their differential responses in all the phagocytic cells considered. In particular, under IONP exposure, the potential occurrence of the GSH-independent antioxidant defense was indicated by the observed herein inhibition in the enzymatic- and thiol-based defense in A. anguilla phagocytes. In contrast, the response of P-, G-, HK-, and S-phagocytes to the increasing Hg exposure period reflected an increased detoxification activity. Notably, the occurrence of an antagonism between IONP and Hg was depicted during late hours (72h) under IONP + Hg concomitant exposure, where elevations in the defense biomarkers were depicted. Overall, the P-, G-, HK-, and S-phagocytic cells exhibited a differential induction in the studied enzymes and thiols to counteract impacts of IONP, Hg, and IONP + Hg concomitant exposures. Future studies on the fish immunotoxicity responses to IONP exposure in multi-pollution conditions can be benefited with the major outcomes of the present study.