Sepsis poses a significant threat to human health due to its widespread prevalence, high mortality rate, substantial treatment costs, and the absence of effective life-saving therapies. Melatonin, a primary hormone regulating the circadian rhythm, has demonstrated potential as a promising therapeutic agent against sepsis. Its anti-inflammatory, antioxidant, immunomodulatory, mitochondrial protective, and multi-organ protective effects are noteworthy. In this review, we summarize current research on the mechanisms of action and clinical efficacy of melatonin in sepsis treatment and multi-organ function preservation, aiming to offer new perspectives and support for sepsis research and therapy.