In recent years, our understanding of sepsis has greatly advanced. However, due to the complex pathological and physiological mechanisms of sepsis, the mechanisms of sepsis are currently not fully elucidated, and it is difficult to translate the research results into specific sepsis treatment methods. Melatonin possesses broad anti-inflammatory, antioxidant, and immune-regulatory properties, making it a promising therapeutic agent for sepsis. In recent years, further research has deepened our understanding of the potential mechanisms and application prospects of melatonin in sepsis. The mechanisms underlying the protective effects of melatonin in sepsis are multifaceted. In this review, based on a substantial body of clinical trials and animal research findings, we first highlighted the significance of melatonin as an important biomarker for disease progression and prognosis in sepsis. We also described the extensive regulatory mechanisms of melatonin in sepsis-induced organ damage. In addition to its broad anti-inflammatory, and anti-oxidant effects, melatonin exerts positive effects by regulating metabolic disorders, hemodynamics, cell autophagy, cellular ion channels, endothelial cell permeability, ferroptosis and other complex pathological mechanisms. Furthermore, as a safe exogenous supplement with low toxicity, melatonin demonstrates positive synergistic effects with other anti-sepsis agents. In the face of the urgent medical challenge of transforming the increasing knowledge of sepsis molecular mechanisms into therapeutic interventions to improve patient prognosis, melatonin seems to be a promising option.