Background: One of the most frequent causes of cerebral palsy (CP) and other neurological severe abnormalities in children is neonatal hypoxic-ischemic encephalopathy (HIE). 1.5 out of every 1000 live births result in neonatal HIE. The degree of brain maturation and the length and intensity of hypoxia determine the pattern of brain injury. Full-term neonates may present with different imaging findings than preterm neonates. Objective: This work aimed to validate tau protein aggregates as an HIE biomarker. Patients and methods: Forty newborns with suspected asphyxia were included in a case-control study that was conducted over 12 months, from February 2022 to February 2023 at the Neonatal Intensive Care Unit of Menoufia University Hospitals. Results: The level of tau protein in patients (163.00 ng/l) was considerably greater than in controls (120.75 ng/l). Tau protein's optimal cutoff point level as a diagnostic marker for HIE cases was > 94.80 ng/l, with a 94.7% specificity and 95.2% sensitivity at an AUC of 0.737. Conclusion: Serum of tau protein levels within the first 24 hours of life can serve as a biomarker for both neurodevelopmental outcomes and an early diagnosis of neonatal HIE.