Objective[|]Cyclophosphamide (CP), as an anticancer agent has side effects, especially hepatotoxicity. Cerium oxide nanoparticles[nanoceria (NC)], which act as antioxidants, have a protective effect against oxidative stress-induced toxicity. This study evaluated the preventive effect of NC in hepatotoxicity induced by CP.[¤]Materials and Methods[|]Thirty-two mice were randomly distributed into four groups: control (received only normal saline), NC (received NC 100 μg/kg for 3 days, intraperitoneally), CP (received CP 200 mg/kg single dose on the third day of the study, intraperitoneally), and NC+CP (NC 100 μg/kg and CP 200 mg/kg). Two days after the final treatment, oxidative stress marker (MDA and GSH) and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels were measured, and histopathological and immunohistochemical examinations were performed for determining the effects of NC on hepatotoxicity.[¤]Results[|]CP-induced hepatotoxicity was evident by the significant elevation of liver enzyme levels and alteration in oxidative stress marker levels. Additionally, histopathological changes and apoptosis were markedly increased. NC decreased MDA level, increased GSH level and decreased liver enzyme levels in CP-treated mice. In addition, NC pretreatment could be alleviated by the immunoreactivity of caspase-3 in CP-treated mice compared with the CP group.[¤]Conclusion[|]NC showed a potent antioxidant effect in hepatotoxicity induced by CP. The study suggested that NC through its antioxidant and anti-apoptotic properties has a protective effect against hepatotoxicity induced by CP.[¤]