Glioblastoma multiforme (GBM) is a lethal and the most common type of primary brain tumor. Extensive hypoxic regions in GBMs turn these tumors highly malignant and worsen the prognosis and clinical outcomes of the patients. Tumor cells residing in hypoxic regions exhibit high ROS levels and resistance to chemo- and radiation therapies. This facilitates the cancer stem cell niche to expand and contribute to cell proliferation and further tumor growth. Therapeutic approaches targeting hypoxia-induced factors, such as the anti-VEGF monoclonal antibody, bevacizumab have shown promising results in stabilizing the disease. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Hence, developing therapeutic approaches that counter hypoxia may hold the key to improving the prognosis and clinical outcome of GBMs. In this work, we report that cerium oxide nanoparticles (CNPs) hold therapeutic potential for the treatment of GBM. CNPs of size 6 nm (CNP-6) and 12 nm (CNP-12) were used for this study. Our results show that CNP-6 exhibits short-term mitigation of ROS levels (up to 24 h) and are able to modulate the TMZ IC50 in tumor microenvironment-like conditions. CNP-12, on the other hand, mitigated ROS levels for up to 72 h, but the mitigation proved to be too lethal for the cells to survive given the important role played by basal-level ROS inside cells. Also, CNP-6 was better at altering metabolic gene expression profile compared to CNP-12 under tumor microenvironment-like conditions. These results indicate that CNPs of size < 10 nm may hold potential for development as nano-therapeutic modalities for tumor treatment. [GRAPHICS] .