Pain and depression are the most common neural responses to many harmful or harmful stimuli. The two are risk factors for each other. The comorbid relationship between pain and depression makes clinical treatment difficult. Seeking an analgesic and antidepressant is an urgent goal of clinical management of pain and depression. Melatonin (N-acetyl-5-methoxytryptamine) secreted by the pineal gland has multiple functions, including anti-inflammatory, antioxidant, immunomodulatory, sedative and analgesic. The effectiveness, safety, and basic non-toxic side effects of melatonin as an analgesic and antidepressant have been demonstrated in various pain animal models, which makes melatonin different in pathological conditions and during surgery. It has been used clinically in patients. Melatonin-mediated analgesic and antidepressant effects may involve inflammatory factors, astrocytes, protein kinase C (PKC) / N-methyl-D-aspartate (NMDA) pathway. However, there are few reports about the mechanism of melatonin in pain syndrome and depression in China. Therefore, this article summarizes the analgesic and antidepressant mechanism of melatonin by consulting domestic and foreign literatures. Provide theoretical basis for clinical treatment of related diseases.