Neonatal jaundice is commonly encountered in the neonatal period. Although it is mostly asymptomatic, severe cases may present as encephalopathy or kernicterus. Hereditary spherocytosis (HS) is the most common cause of nonimmune hemolytic anemia and the third most common cause of kernicterus after glucose-6-phosphate-dehydrogenase deficiency and ABO isoimmunization. Awareness of the clinical presentation and the laboratory tests necessary to diagnose the disease can lead to early detection and effective interventions, thereby preventing adverse outcomes. This article focuses on HS: its pathophysiology, clinical presentation in the neonatal period, natural history, and the relevant diagnostic features of evaluation.