Melatonin, a potent free radical scavenger, plays an important role in homeostasis of cell and organ physiology. The increased demand and synthesis from the pineal gland during times of oxidative stress suggests a potential benefit of melatonin supplementation during hospitalization for acute illness. Yet, the paucity of clinical studies for non-anesthetic-associated indications in pediatric populations hampers the safe, effective, and consistent use of melatonin. The objective of this study was to systematically review published studies of melatonin use for non-sedative and non-analgesic indications in hospitalized pediatric patients. We conducted a search of PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Scopus databases for articles on the use of melatonin for pediatric patients in a hospital setting. Thirteen eligible studies, all in neonates, were identified. Data elements extracted included study design, number of study subjects, indication for melatonin therapy, and melatonin regimen (formulation, dosage, and duration). Because study methodologies were very heterogeneous, a quantitative synthesis of the published findings was not possible. The identified studies were therefore categorized by the indication of melatonin (adjuvant-antioxidant or anti-inflammatory therapy) in the following specific disease states: (i) acute infections, (ii) respiratory distress syndrome, (iii) neurologic injury, and (iv) jaundice. The current data suggest that melatonin is safe for use in hospitalized neonates. Melatonin may be beneficial for reducing inflammatory markers in neonatal patients with disease states and clinical sequelae that are associated with increased inflammation and oxidative stress. Melatonin, in conjunction with phototherapy, is not superior to use of vitamin D with phototherapy for treatment of neonatal jaundice. However, studies in other pediatric populations are needed given widespread use across clinical inpatient settings. © 2020 Pharmacotherapy Publications, Inc.