Hypoxic–ischemic encephalopathy (HIE) is one of the leading causes of acute neonatal death and chronic neurological damage, and severe HIE can have secondary sequelae such as cognitive impairment and cerebral palsy, for which effective interventions are lacking. In this study, we found that continuous 30-day intake of Acer truncatum Bunge seed oil (ASO) reduced brain damage and improved cognitive ability in HIE rats. Using lipidomic strategies, we observed that HIE rats had decreased unsaturated fatty acids and increased lysophospholipids in the brain. However, after 30 days of ASO treatment, phospholipids, plasmalogens, and unsaturated fatty acids increased, while lysophospholipids and oxidized glycerophospholipids decreased in both serum and the brain. Enrichment analysis showed that ASO intake mainly affected sphingolipid metabolism, fat digestion and absorption, glycerolipid metabolism and glycerophospholipid metabolic pathways in serum and the brain. Cluster, correlation, and confirmatory factor analyses showed that cognitive improvement after ASO administration was attributed to increased essential phospholipids and ω3/6/9 fatty acids, coupled with decreased oxidized glycerophospholipids in HIE rats. Our findings indicate that ASO has the potential to be developed as an effective food supplement for ischemic hypoxic newborns.