Owing to the autocatalytic antioxidant activity, cerium oxide nanoparticle (CeNPs) has been extensively used in biomedical fields for treatment of neurodegenerative diseases, biosensing, and therapeutic applications. The redox-dependent interconversion between +3 and +4 oxidation states of CeNPs is suggested to be the reason of scavenging of free radical generated in the biological system. Herein we have explored the protective effect of CeNPs against the oxidative stress induced by organophosphate-based pesticide, 2,2-dichlorovinyl dimethyl phosphate (DDVP), in a normal human liver cell culture model (WRL-68). DDVP is known to cause the toxic effect in cells by inducing lipid peroxidation, cellular glutathione level depletion and DNA fragmentation by the caspase-dependent pathway. We followed the protection of cells by CeNPs against DDVP exposure using MTT and NRU assays. Exposure of DDVP to cells induced significant nuclear fragmentation, which could be avoided in cells pre-treated with CeNPs. Mechanistically, we observed that CeNPs induces an increase in cellular GSH level, which could assist in removal of excess of reactive oxygen species, generated in DDVP exposed cells, along with the superoxide dismutase (SOD)-like activity of CeNPs. The interaction study showed that there was no chemical interaction between DDVP and CeNPs, therefore, the intrinsic SOD-like activity of CeNPs was intact even in the complex cell culture media. Growing evidence suggest that excess use of DDVP could lead to the several diseases in cells/tissues, therefore our finding emphasizes that CeNPs can be used as a potent antioxidant agent to avoid the ramifications of DDVP and other commercial pesticides.