Glioma is a primary brain tumor with high frequency and dismal prognosis. As there is no permanent cure available, identifying new therapy or mediator to augment the effectiveness of existing therapy is urgently needed. In the current study we tested the effect of group I metabotropic glutamate receptors (mGluRs): mGluR1 and mGluR5 on the viability of glioma cell lines. We analyzed cell viability using lactate dehydrogenase (LDH) release assay and evaluated apoptosis by propidium iodide (PI) staining. We used qPCR to evaluate change in mitochondrial gene expression and Western blot to evaluate the phosphorylation of Akt and ERK. Inhibition of mGluR5 by a selective antagonist MPEP under hypoxia promoted cell death, and induced expression of mitochondrial oxidative function related genes, with concurrent lowering of AKT phosphorylation level in glioma cell lines. Akt activation reversed mGluR5 inhibition on hypoxia-induced glioma cell death. These results suggest mGluR5 as a potential therapeutic target for hypoxic tumors such as malignant glioma.