Hypoxic-ischemic brain damage (HIBD) is a severe condition leading to extensive neuronal loss and functional impairments, representing a significant challenge in neonatal care. PFGA12, a peptide derived from fibrinogen alpha chain (FGA), which is notably downregulated in the umbilical cord blood of hypoxic-ischemic encephalopathy (HIE) infants. We demonstrate that PFGA12 significantly enhances cell viability and mitigates oxygenglucose deprivation/reperfusion (OGD/R)-induced neuronal cell death. PFGA12 treatment significantly alleviated cerebral edema, reduced infarct volume, and attenuated neuronal damage in HIBD rats, attributable to its stable presence within neurons. Additionally, PFGA12 attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Moreover, Y-maze test demonstrated that PFGA12 effectively improved the spatial learning and memory abilities. Mechanistically, PFGA12 exerts potent neuroprotective effects by specifically targeting peroxiredoxin-1 (PRDX1). PFGA12 directly binds to PRDX1, effectively inhibiting phosphorylation at Tyr194 (p-PRDX1), thereby enhancing its peroxidase activity. This PRDX1-mediated antioxidant mechanism substantially reduces lipid reactive oxygen species (ROS) accumulation and provides protection against OGD/Rinduced neuronal ferroptosis, as demonstrated by the upregulation of Glutathione peroxidase 4 (GPX4) and suppression of Acyl-CoA synthetase long-chain family member 4 (ACSL4). Notably, overexpression of PRDX1 mitigates ferroptotic damage induced by OGD/R, while knockdown of PRDX1 completely abolishes the protective effects of PFGA12 in OGD/R-treated HT22 cells, confirming PRDX1 as the critical molecular target through which PFGA12 inhibits ferroptosis. These results demonstrate that PFGA12, an active peptide, exhibits potential as a novel treatment option for HIBD.