Global cerebral ischemia (GCI), a consequence of cardiac arrest (CA), can significantly damage the neurons located in the vulnerable hippocampus CA1 areas. Clinically, neurological injury after CA contributes to death in most patients. Mastoparan-M extracted from Vespa magnifica (Smith) can be used to treat major neurological disorders. Hence, this study aimed to assess the effects of Mastoparan-M on GCI.To evaluate the neurotoxicity and neuroprotective effect of Mastoparan-M, the CCK8 and Annexin V-FITC/PI apoptosis assays were first performed in hippocampal HT22 neuronal cells in vitro. Then, Pulsinelli's 4-vascular occlusion model was constructed in rats. After treatment with Mastoparan-M (0.05, 0.1, and 0.2 mg/kg, IP) for 3 or 7 days, behavioral tests, H&E staining or Nissl staining, immunohistochemistry, and ELISA were employed to investigate neuroprotective effects of Mastoparan-M on GCI in rats.In vitro, the growth of HT22 neuronal cells was restrained at concentrations of 30-300 µg/ml (at 24 hr, IC50=105.2 µg/ml; at 48 hr, IC50=46.81 µg/ml), and Mastoparan-M treatment (0.1,1 and 5 µg/ml) restrained apoptosis. In vivo, Mastoparan-M improved neurocognitive function and neuronal loss in the hippocampal CA1 area of rats. In addition, these effects were associated with the prevention of neuroinflammation, oxidative stress, and apoptosis.Mastoparan-M acts as a neuroprotective agent to alleviate neuronal death in rats.