An abrupt increase of intracellular $Ca^{2+}$ is observed in cells under hypoxic or oxidatively stressed conditions. The dysregulated increase of cytosolic $Ca^{2+}$ triggers apoptotic cell death through mitochondrial swelling and activation of $Ca^{2+}$-dependent enzymes. Transglutaminase 2 (TG2) is a $Ca^{2+}$-dependent enzyme that catalyzes transamidation reaction producing cross-linked and polyaminated proteins. TG2 activity is known to be involved in the apoptotic process. owever, the pro-apoptotic role of TG2 is still controversial. In this study, we investigate the role of TG2 in apoptosis induced by $Ca^{2+}$-overload. verexpression of TG2 inhibited the A23187-induced apoptosis through suppression of caspase-3 and -9 activities, cytochrome c release into cytosol, and mitochondria membrane depolarization. Conversely, down-regulation of TG2 caused the increases of cell death, caspase-3 activity and cytochrome c in cytosol in response to $Ca^{2+}$-overload. Western blot analysis of Bcl-2 family proteins showed that TG2 reduced the expression level of Bax protein. Moreover, overexpression of Bax abrogated the anti-apoptotic effect of TG2, indicating that TG2-mediated suppression of Bax is responsible for inhibiting cell death under $Ca^{2+}$-overloaded con conditions. Our findings revealed a novel anti-apoptotic pathway involving TG2, and suggested the induction of TG2 as a novel strategy for promoting cell survival in diseases such as ischemia and neurodegeneration.