Introduction : Perinatal asphyxia is a challenge to the survival of the fetus or the newborn due to lack of oxygen (hypoxia) and/or lack of perfusion (ischemia) to various organs. In a country like India when home deliveries are predominant the infant mortality rate is also equally high. The common denominator of hypoxic ischemic injury is deprivation of the supply of oxygen to the central nervous system. An oxygen deficit may be incurred by either hypoxemia or ischemia. Hypoxemia is defined as a diminished oxygen content of the blood and ischemia is characterized by reduced perfusion of that particular tissue; generally the two tend to occur simultaneously or in sequence. Asphyxia is an impairment of gas exchange that results not only in the deficit of oxygen in blood but also an excess of carbon dioxide causing acidosis. The acidosis further leads to hypotension and ischemia culminating in hypoxic-ischemic injury. Hypoxic- ischemic encephalopathy (HIE) invariably leads to permanent damage to CNS tissues that may result in neonatal death or manifest later as cerebral palsy or developmental delay. Aim &objective: To estimate and compare the serum levels of Neuron specific enolase (NSE), Creatine Kinase-Muscle Brain fraction ( CK-MB), Lactate Dehydrogenase (LDH), SGOT, SGPT, urea, creatinine in HIE and non-HIE term neonates. Method: This prospective study was conducted from December 2017 to June 2019 study in the department of Biochemistry and department of Pediatrics Department of Pediatrics, S C B Medical College, Cuttack. Observation: Mean serum level of neuron specific enolase (NSE) among control group of neonate was 16.65ng/ml with a 95% CI of 15.02 ng/ml to 18.27 ng/ ml with a width of 1.63 ng/ml which is statistically significant from the mean serum level of the case group of neonate. The diagnostic performance of CK-MB in differentiating HIE from non-HIE is excellent with a sensitivity of 78.6%, specificity and PPV of 100%, a NPV of 82.4% and area under ROC curve of 0.968 when the sample was drawn at 6-12 hours of life. Conclusion: The biochemical marker like CK-MB,LDH and NSE can help to institute early neuroprotective measures for better neonatal outcome in case when proper history of hypoxic ischemic encephalopathy is not available.