<p>Hypoxic-ischemic brain damage (HIBD) is a primary cause of neonatal neurological dysfunction, such as cerebral palsy, characterized by complex cascades of neuronal death. Despite the urgent need, effective therapeutic strategies are scarce, and the efficacy of standard interventions, such as therapeutic hypothermia, remains limited. Astragaloside IV (AS-IV), a promising neuroprotective agent, is hindered from wide clinical applications by poor permeability across the blood–brain barrier (BBB) and low bioavailability. To overcome this bottleneck, we developed a novel targeted delivery system based on neural stem cell-derived extracellular vesicle, designated AS-EV, which efficiently deliver AS-IV to the HIBD-affected brain region. AS-EV were successfully prepared via ultracentrifugation and sonication-loading, exhibiting typical exosomal characteristics, and favorable drug-loading efficiency. In vivo experiments confirmed that AS-EV effectively crossed the BBB to accumulate in the injured brain region with satisfying biocompatibility. Mechanistic investigation using primary cortical neurons revealed that the core therapeutic mechanism of AS-EV is mediated by mTOR activation, which consequently suppressed HIBD-induced neuronal apoptosis, an effect that was abrogated by mTOR inhibition. Furthermore, functional and histological assessments demonstrated that AS-EV intervention significantly promoted neurological function recovery, alleviated brain tissue pathology, protected white matter integrity, facilitated neural structural remodeling, and inhibited glial scar proliferation in neonatal HIBD rats. In conclusion, NSC-EV-mediated delivery of AS-IV exerts multifaceted neuroprotective and reparative effects by activating the mTOR pathway, offering a promising therapeutic strategy for HIBD.</p>