Neonatal hypoxic-ischemic encephalopathy (HIE) is an ongoing process, which may persist for weeks to years after an acute asphyxial insult, causing delayed programmed cell death. The typical clinical signs and the pathological findings of HIE manifest as the condition evolves in a step-wise manner, beginning with an acute phase, followed by a latent, a secondary energy failure phase, and eventually a tertiary brain injury phase. To date, therapeutic hypothermia (TH) is the only effective treatment strategy known to improve mortality and prevent neurodevelopmental disabilities, as has been proven by the results of several randomized controlled clinical trials. The current protocols describing the use of TH for newborns of gestational age ≥36 weeks with HIE, associated with clinical evidence of asphyxia along with neurological signs of moderate-to-severe encephalopathy, observed at ≤6 hours of age, are close to optimal. Most comorbid conditions observed during TH are related to asphyxia. TH is a safe treatment option—benign sinus bradycardia and thrombocytopenia are frequent hypothermia-related complications. Additional adjuvant agents, which may augment hypothermic neuroprotection are being investigated, and a few of them, such as erythropoietin and melatonin appear to be promising agents for use in this condition. Establishing our own nationwide cooling systems and guidelines for a standard treatment protocol to manage HIE are warranted in the future.