Background: Today, magnesium oxide nanoparticles (MgO NPs) have been introduced as a promising material into industry, medicine, and research. However, there are growing concerns about the toxicity of MgO NPs as they induce oxidative stress and cell death. Coating MgO NPs with cerium oxide (CeO2), as an antioxidant, might prove useful to reduce the oxidative damages caused by NPs. Objective: This study aimed at synthesizing MgO/CeO2 core/shells to reduce the in vitro and in vivo toxicity of MgO NPs. Methods: Herein, the cytotoxic impacts of MgO NPs, MgO/CeO2 (0.05/0.05) and (0.05/0.01) core/shell NPs on cell viability (MTT assay), cell death (Annexin V flow cytometry assay), oxidative damages (measurement reactive oxygen species (ROS), and lipid peroxidation (LPO)) were evaluated in pheochromocytoma (PC12) and fibroblast cell line (3T3) cell lines. For the in vivo study, the mice were given an intraperitoneal injection of NPs (50 mg/kg) for 10 days to evaluate the liver and kidney toxicity parameters. Results: In the in vitro study, the IC50 values of MgO NPs, MgO/CeO2 (0.05/0.05), and MgO/CeO2 (0.05/0.01) core/shell were 102.6, 408, and 198 & mu;g/ml in 3T3 cell line and 47, 409, and 156 & mu;g/ml in PC12 cell line, respectively. Also, MgO/CeO2 (0.05/0.01) core/shell reduced apoptotic and necrotic cell death and cellular oxidative stress. In the in vivo study, histological changes in the liver and kidney tissues caused by MgO NPs were not observed in the mice treated with MgO/CeO2 (0.05/0.01) core/shell. Also, LPO in the serum samples of the mice receiving MgO/CeO2 (0.05/0.01) core/shell was lower than that in the serum samples of the mice treated with MgO NPs. Discussion and conclusion: CeO2 coating seems to decrease the cytotoxicity of MgO NPs by inhibiting oxidative damage. The preparation of MgO/CeO2 core/shells could be a novel strategy to produce safer products of MgO NPs to be used in the pharmaceutical industry and the water purification process.