Sepsis is an uncontrolled host response to infection. In some cases, it progresses to multi-organ insufficiency, leading to septic shock and increased risk of mortality. Various organ support strategies are currently applied clinically, but they are still inadequate in terms of reducing mortality. Melatonin is a hormone that regulates sleep and wakefulness, and it is associated with a reduced risk of death in patients with sepsis. Evidence suggests that melatonin may help protect organ function from sepsis-related damage. Here, we review information related to the role of melatonin in protecting organ function during sepsis and explore its potential clinical applications, with the aim of providing an effective therapeutic strategy for treating sepsis-induced organ insufficiency.