Neuronal vulnerability to ischemia is dependent on the balance between pro-survival and pro-death cellular signaling. In the latter, it is increasingly appreciated that toxic Ca2+ influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a non-specific cation channel having similar homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca2+ influx has been difficult to study due to the lack of specific modulators. Here we used TRPM2-null mice (TRPM2(-/-)) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2(-/-) mice subjected to transient middle cerebral artery occlusion (tMCAO) exhibited smaller infarcts when compared to wild-type (WT) animals, suggesting the absence of TRPM2 to be protective. Surprisingly, field potentials (fEPSPs) recorded during oxidative stress in brain slices taken from TRPM2(-/-) mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas WT fEPSPs were unaffected. The upregulation in fEPSP in TRPM2(-/-) neurons was blocked selectively by an NR2A antagonist. This oxidative stress-induced increase in excitability of TRPM2(-/-) fEPSPs depended on the upregulation and downregulation of NR2A and NR2B-containing NMDARs, respectively, and augmented pro-survival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor, GSK3β. Cultured hippocampal neurons from TRPM2(-/-) animals subjected to oxygen glucose deprivation had a reduction in cell death in comparison to WT neurons, demonstrating that absence of TRPM2 is protective at the neuronal level in vitro. Our results suggest that TRPM2 plays a role in downregulating pro-survival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage.