This study aims to investigate the protective effect and underlying mechanism of eriodictyol (Eri) in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE). Neonatal rats were randomly assigned to control, HIE, or Eri groups. Seven-day-old rats was induced to HIE via right common carotid artery ligation with hypoxia. The Eri treatment group was administrated 20 mg/kg Eri daily for seven days. At the end of postnatal day 21, spatial learning and memory were assessed by the Morris water maze. On day 26, brains were collected for HE, Nissl, and TUNEL staining. The levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and brain-derived neuotrophyic factor (BDNF) in the cerebral cortex were measured by Western blot. Additionally, the expression of tight junction proteins of the blood-brain barrier, such as Claudin, Occludin, and zonula occludens-1 (ZO-1), wingless-type MMTV integration site family 3a(Wnt3a), glycogen synthase kinase-3β(GSK-3β), β-catenin were also detected. It was demonstrated that Eri improved learning and memory in HIE rats (P<0.05 or P<0.01). HE and Nissl staining revealed reduced necrotic brain tissue degeneration, while TUNEL staining showed a significant decrease in neuronal apoptosis. Furthermore, Eri reduced the expression of IL-1β, TNF-α, and GSK-3β (P<0.05 or P<0.01), while increased BDNF, Claudin, Occludin, ZO-1, Wnt3a, and β-catenin in HIE rats (P<0.05 or P<0.01). In summary, Eri improved cognitive function, alleviated neuroinflammation and cell apoptosis, and promoted blood-brain barrier repair in HIE model, which potentially mediated by the Wnt/GSK-3β/β-catenin signal pathway.