Background: In neonates with moderate-to-severe hypoxia-ischemia encephalopathy (HIE), Therapeutic hypothermia (TH), which can be achieved by either whole-body or localized head cooling, lessens brain damage, offers neuroprotection, and lowers mortality rates, especially if initiated within the first six hours after birth. Moreover, adjuvant therapy like magnesium sulfate (MS) management offers increased neuroprotection. The goal of the interventional, randomized, controlled study was to evaluate the short-term effects of using TH alone or in conjunction for the treatment of newborn infants with MS as a neuroprotective medication with HIE. Aim: to evaluate the effects of whole-body cooling and magnesium sulfate on infants with hypoxic-ischemic encephalopathy treatment. Patients and methods: 39 newborns who met the HIE criteria and were born in the Neonatal Intensive Care Unit at Sohag University Hospital were enrolled in the study. They were split equally across the three groups; During the first six hours of life, Group 1 (n 13) received whole-body cooling as the only therapy; In addition to MS, Group 2 (n 13) received whole-body cooling as adjuvant therapy, while Group 3 (n 13) received supportive acute care interventions as a comparison. Results: The TH plus MS group (group 2) had significantly better short-term outcomes when compared to other groups managed by TH (group 1) or supportive treatment, as indicated by a brief period of mechanical ventilation and respiratory support (p-value 0.001), a decrease in the incidence of convulsions (p-value 0.001), and an early start to feeding (p-value 0.001) (p-value 0.009) (group 3). Conclusion: In addition to MS, total body cooling is a safe therapy that enhances short-term clinical and radiological outcomes for the treatment of HIE infants. In neonates with moderate-to-severe hypoxia-ischemia encephalopathy (HIE), Therapeutic hypothermia (TH), which can be achieved by either whole-body or localized head cooling, lessens brain damage, offers neuroprotection, and lowers mortality rates, especially if initiated within the first six hours after birth. Moreover, adjuvant therapy like magnesium sulfate (MS) management offers increased neuroprotection. The goal of the interventional, randomized, controlled study was to evaluate the short-term effects of using TH alone or in conjunction for the treatment of newborn infants with MS as a neuroprotective medication with HIE. Aim: to evaluate the effects of whole-body cooling and magnesium sulfate on infants with hypoxic-ischemic encephalopathy treatment. Patients and methods: 39 newborns who met the HIE criteria and were born in the Neonatal Intensive Care Unit at Sohag University Hospital were enrolled in the study. They were split equally across the three groups; During the first six hours of life, Group 1 (n 13) received whole-body cooling as the only therapy; In addition to MS, Group 2 (n 13) received whole-body cooling as adjuvant therapy, while Group 3 (n 13) received supportive acute care interventions as a comparison. Results: The TH plus MS group (group 2) had significantly better short-term outcomes when compared to other groups managed by TH (group 1) or supportive treatment, as indicated by a brief period of mechanical ventilation and respiratory support (p-value 0.001), a decrease in the incidence of convulsions (p-value 0.001), and an early start to feeding (p-value 0.001) (p-value 0.009) (group 3). Conclusion: Magnesium sulfate and total body cooling is a safe therapy that enhances short-term clinical and radiological outcomes for the treatment of HIE infants.