Background: Cerium oxide or ceria (CeO2), a rare earth metal oxide. CeO2 nanoparticles (CNPs) have received much attention in nanotechnology due to their useful applications as catalysts, fuel cells and antioxidants in biological systems [1]. CNPs, exhibit biomimetic properties depending on their size, ratio of valency on their surface, and the ambient physico-chemical properties. Aim: To evaluate the. cytotoxic effect of CNPs on U251 cells at pH 7.4 under normoxia (physiological) and pH 6.5 under 1.5% physiological hypoxia (tumor micro-environment) conditions. Methods: The CNPs were synthesized at 6nm (CNP-6) and 12nm (CNP-12) sizes, characterized and glioma cell lines were treated with these CNPs at varying concentration. The cytotoxicity assay was performed (MTT assay). Then IC50 value was determined and the GBM cells were treated with CNP-6 and CNP-12 under physiological and tumor micro-environment. Total RNA was extracted, converted to cDNA and Real-time PCR was done to determine the gene expression pattern of several metabolic genes. Results: These CNPs also had a modulating effect on metabolic gene (GLUT 1, 3, 4, PKM, PFKP, MCT1, 4) expression. In addition, The CNPs also exhibited peroxidase-like activity thus sensitizing the tumor cells towards chemotherapy, thus suggesting a promising tool for cancer therapy.