Cerium oxide nanoparticles (CeO NPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to elucidate whether CeO NPs can prevent or attenuate oxidant injury in the hepatic human cell line HepG2 and to investigate the mechanisms involved in this phenomenon. The effect of CeO NPs on cell viability and ROS scavenging was determined, the differential expression of pro-inflammatory and oxidative stress-related genes was analyzed, and a proteomic analysis was performed to assess the impact of CeO NPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeO NPs did not modify HepG2 cell viability in basal conditions but reduced H O-and lipopolysaccharide (LPS)-induced cell death and prevented H O-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeO NPs reverted the H O-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with H O effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeO NPs protect HepG2 cells from cell-induced oxidative damage, reducing ROS generation and inflammatory gene expression as well as regulation of kinase-driven cell survival pathways.