Background: Any illness that disrupts the central nervous system in the first few days of life can induce encephalopathy among neonates. This ailment can have a variety of causes. Of all the CSF neurobiochemical markers in babies with HIE, NSE has received the greatest amount of research. Up to four percent of all soluble brain proteins are NSE, a dimeric glycolytic enzyme. Neurons and neuroendocrine cells contain it primarily in their cytoplasm. When neurons suffer damage to their axons, NSE is found in high concentrations in their cytoplasm. Thus, it is sensitive for axonal injury and neuronal cell death and has a fairly high specificity for detecting axonal damage. Traditional terminology for neonatal encephalopathy (NE) has focused on hypoxic-ischemic encephalopathy, which occurs when an intrapartum incident causes perinatal hypoxia-ischemia. Objective: The purpose of this study was to review the diagnostic value of the Neuron-Specific Enolase biomarker in the evaluation of early detection and its role in prognosis of neonatal encephalopathy. Methods: In our search for information on NSE and its level in neonates with encephalopathy, we used Google Scholar, Science Direct, PubMed, and other internet databases. Additionally, the writers combed through relevant literature for references, however they only included researches that were either very recent or covering the years from 2010 to 2023. Conclusion: Serum NSE is considered to be a reliable marker for the diagnosis of different stages of NE.