Neonatal indirect hyperbilirubinemia (IHB) is caused by an imbalance in bilirubin production and elimination. Approximately 60% of term and 80% of preterm infants develop jaundice in the first week of age. This review seeks to provide the reader with a thorough understanding of the physiology of bilirubin, etiology of IHB, and management of severe IHB. Phototherapy and exchange transfusion remain the mainstays of treatment for severe IHB. Noninvasive screening tools, innovative treatments, and a better understanding of how prematurity and genetics contribute to severe IHB have improved our understanding of IHB and may help eliminate the hazards associated with severe IHB, including kernicterus spectrum disorder.