Aim: To study the synergistic anti-glioma efficacies of Temozolomide, Metformin and Epigallocatechin Gallate in U87MG and C6 glioma cells. Background: Glioblastoma (GBM) is the most malignant and invasive tumor of the central nervous system. The current standard treatment comprises surgical resection, followed by adjuvant radiotherapy and chemotherapy employing temozolomide (TMZ). Yet the survival rates for GBM patients is very low. Hence there is a need for new treatment regimes Objective: This study was aimed to unravel the synergistic anti-tumor potential of a biguanide drug, Metformin (MET) and a polyphenol, Epigallocatechin gallate (EGCG) to enhance the anti-GBM efficacy of the standard drug. Methods: Anti-proliferative effect of TMZ, MET and EGCG, individually and in combination was elucidated in U87MG (human) and C6 (rat) glioma cells using MTT assay and combination index was used to determine synergism. Cytotoxicity of the drugs was performed in HEK293T noncancerous cells. Apoptotic morphological changes in the cells were observed by AO/EtBr staining. Further, the effect of drugs on antioxidant and apoptotic genes (SOD, CAT, Nrf-2, Caspase-9 and Bcl-2) were evaluated using qRT-PCR and the protein levels of Nrf-2 and Caspase-9 was evaluated using ELISA. Results: The triple-drug combination (TMZ+ MET+ EGCG) synergistically inhibited the proliferation of U87MG and C6 glioma cells in a dose-dependent manner and promoted the apoptosis of glioma cells. The triple-drug combination significantly up-regulated the expression of antioxidant and apoptotic genes and induced oxidative stress suggesting a shift in equilibrium towards apoptosis. Conclusion: MET and EGCG in combination with TMZ synergistically promoted oxidative stress induced apoptosis in glioma cells. Hence, the combination of TMZ, MET and EGCG may be therapeutically exploited for improving the clinical outcomes of patients with GBM.