Pharmacoresistant epilepsy is estimated to affect about 30% of patients with epilepsy and predisposes to a higher risk for psychiatric comorbidities and depression. This is one of the most common complications in epilepsy but the mechanisms underlying its development are still unclear. Periclinical studies have shown that selective serotonin reuptake inhibitors (SSRIs) are ineffective against comorbid depression. Dysfunction in circadian rhythms which are driven by the suprachiasmatic nucleus (SCN), is a hallmark of depression. The activity of this circadian pacemaker is under the fine-tuning control of the endogenous hormone melatonin. Over the past decade, there has been extensive research on the therapeutic potential of melatonin and its analogues in the management of both epilepsy and depressive disorders. Melatonin and its analogues targeting the melatonin MT1 and MT2 receptors are considered as potential adjuvants for the treatment of epilepsy associated with moderate-to-strong antioxidant, anti-inflammatory, and neuroprotective activity at non-toxic doses. One of the main advantages of the melatonin system is associated with its chronobiotic properties and pivotal role in the resynchronization of disturbed circadian rhythms of different parameters. This chapter summarizes the available experimental and clinical data on melatonin and drugs acting on the MT receptors, which are currently of therapeutic interest in the treatment of epilepsy and depression. Despite the fact that melatonin and drugs based on MT receptors have been used for many purposes over the last three decades, the available data on the potential implementation of melatonin compounds in epilepsy and comorbid depression are scarce. The many unanswered questions regarding the use of melatonin to treat epileptic seizures and complications associated with epilepsy are briefly summarized.