Hypoxic-ischemic encephalopathy (HIE) is a prominent cause of neuronal damage and neonatal death, and effective treatment strategies remain limited. In a prior investigation, we purified a novel peptide (designated MIP-15) from the rare mushroom Morchella importuna, demonstrating its notable free radical scavenging activity. Nevertheless, the potential neuroprotective role of MIP-15 in neonatal hypoxic-ischemic brain damage (HIBD) and its underlying mechanism remain elusive. The purpose of this study was to evaluate whether MIP-15 exerts neuroprotective effects by inhibiting the mitochondrial apoptotic pathway after HIBD. A HIBD model in 7-day-old (P7) rats was established by the Rice-Vannucci method to evaluate the effect of MIP-15 on the neurological damage severity and space cognitive ability of rats. Subsequently, an oxygen glucose deprivation/reoxygenation (OGD/R) model was established in rat primary hippocampal neurons to explore the mechanism of MIP-15 action. Both in vivo and in vitro data showed that MIP-15 markedly restored endogenous antioxidative activity, decreased brain water content, and ameliorated pathological abnormalities following HIBD. The spatial cognitive ability and motor function of HIBD rats were also repaired. Moreover, in primary hippocampal neurons after OGD/R, MIP-15 increased cell viability by inhibiting the mitochondrial-dependent apoptosis pathway, as manifested by stabilization of the mitochondrial membrane potential, prevention of the release of cytochrome c, upregulation of Bcl-2/Bax, and reduction in the triggering of caspase proteins. These data indicate that MIP-15 may have the potential to act as a neuroprotective agent.