Given the devastating social and health consequences of drug addiction and the limitations of current treatments, a new strategy is needed. Circadian system disruptions are frequently associated with drug addiction. Correcting abnormal circadian rhythms and improving sleep quality may thus be beneficial in the treatment of patients with drug addiction. Melatonin, an essential circadian hormone that modulates the biological clock, has anti-inflammatory, analgesic, anti-depressive, and neuroprotective effects via gut microbiota regulation and epigenetic modifications. It has attracted scientists' attention as a potential solution to drug abuse. This review summarized scientific evidence on the roles of melatonin in substance use disorders at the cellular, circuitry, and system levels, and discussed its potential applications as an intervention strategy for drug addiction.