Neonatal encephalopathy (NE) is defined as a condition of impaired neurological function often caused by a peripartum event that impairs gas exchange resulting in hypoxia, hypercapnia, cerebral ischemia, and metabolic acidosis. NE is a significant cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH) is the standard of care for the treatment of moderate and severe NE and has significantly improved long-term outcomes for affected infants. There are extensive systemic physiologic effects associated with TH that clinicians need to be aware of to optimize care for these infants. There is a paucity of literature that comprehensively identifies causal relationships between the physiologic and biochemical effects of TH. This can leave neonatal clinicians devoid of a comprehensive understanding of the medical management of NE. Therefore, this article seeks to help fill this gap, improve clinician knowledge base, and ultimately improve the care of infants undergoing TH.