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Sepsis represents a major clinical problem in neonatal setting with elevated mortality rate related to multiple organ failure. Despite decades of research, the exact mechanism of organ failure in sepsis is still not completely understood. Oxidative stress (OS), derived from an imbalance between pro-oxidant and antioxidant factors, is involved in the pathogenesis of several neonatal diseases, including sepsis, and plays a particular role in systemic organ failure. Recently, it has been recognized that administration of antioxidants could be useful in septic patients. Among all antioxidants, melatonin has a characteristic role as an antioxidant, anti-inflammatory, and anti-apoptotic agent. In combination with other interventions, melatonin may contribute to an improvement in septic organ injury. Furthermore, melatonin has already been widely used in treating various diseases of neonatal population, including asphyxia, respiratory distress, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. This review aims to summarize current knowledge concerning the potential beneficial role of melatonin in septic neonates, supporting its short-term adjuvant co-therapy to reduce complications during neonatal sepsis.