Depression exists as Major Depressive Disorder (MDD) or bipolar disorder, each identified by neurobiological manifestations that affect therapeutic and prognostic approaches. The etiology of depression is multifaceted, involving genetic, environmental, psychological, and behavioral factors. Sleep disturbances, particularly insomnia, are common in depression, and are often assessed using the Hamilton Depression Rating Scale. Polysomnographic studies have shown alterations in both slow-wave sleep and rapid eye movement sleep in depressed individuals, highlighting the role of circadian rhythm-based treatments. Melatonin, a hormone closely linked to circadian rhythms, is synthesized from tryptophan and regulated by the suprachiasmatic nucleus. It also affects clock genes expression by inhibiting proteasome activity. Exogenous administration of melatonin has been revealed to adjust circadian phases, suggesting its potential in treating sleep disorders and reducing insomnia linked with depression. This article aimed to examine the preclinical and therapeutic impacts of agonists of melatonin receptor, like agomelatine and ramelteon, on depression. The detected reduction in melatonin production in patients with depression underscores the potential relevance of these treatments. Clinical studies have showed the antidepressant effects of melatonin, with affirmation from both animal models and human MDD patients. Despite that, the complex role of melatonin in depression needs further investigation. Melatonin interacts with norepinephrine and serotonin, influencing norepinephrine availability. It has been shown to inhibit norepinephrine release, and the elevated melatonin levels observed in some depressed patients have prompted investigation into melatonin reduction strategies. Melatonin antagonists, such as Luzindole, 4-phenyl-2-propionamidotetraline, and 4-phenyl-2-acetamidotetraline, show promise as novel antidepressants.