Cerium oxide nanoparticles (CeONPs) possess unique physicochemical properties that make them promising compounds for medical and industrial applications. However, variations in synthesis methods, particle size, and surface characteristics may influence their potential toxicity. This study provides a comparative analysis of CeONPs synthesized via three methods (citric, dextran, and uncoated modifications) to evaluate their toxicity, antioxidant mechanisms, and genoprotective potential using a panel of -based lux-biosensors. Our data indicate that all of the tested CeONPs exhibit high biocompatibility with no significant toxicity or genotoxicity at physiological concentrations (10-10 M). The citrate-modified nanoparticles demonstrated pronounced catalase-mimetic activity, acting as the most effective scavengers against hydrogen peroxide. Conversely, the dextran-modified nanoparticles exhibited the highest antimutagenic potential, reducing dioxidine-induced DNA damage by over 56%. Thus, beyond establishing biocompatibility, this study highlights the potential of using specific CeONP modifications for targeted therapy depending on the oxidative pathway involved. This suggests their potential for application as antioxidant and antimutagenic agents in both human and veterinary medicine.