This review aims to synthesize current evidence on the role of melatonin in glaucoma pathophysiology, its relationship with sleep disturbances and circadian dysregulation, and its potential as a therapeutic agent beyond intraocular pressure (IOP) control. Glaucoma is a chronic neurodegenerative optic neuropathy characterized by progressive retinal ganglion cells (RGCs) loss. While IOP remains the primary modifiable risk factor, disease progression often persists despite adequate pressure control, highlighting the need for adjunctive neuroprotective strategies. Sleep disturbances are highly prevalent in glaucoma and may reflect underlying circadian dysfunction. This review integrates findings from clinical, experimental, and translational studies, including observational cohorts, meta-analyses, and mechanistic investigations of melatonin signaling, receptor distribution, and therapeutic modulation. Melatonin secretion is significantly reduced in glaucoma, particularly in advanced stages, as demonstrated by urinary 6-sulfatoxymelatonin levels. Melatonin receptors 1 and 2 are expressed in multiple ocular tissues, including RGCs, photoreceptors, and the ciliary body, mediating circadian regulation, antioxidant defense, and IOP modulation. Melatonin deficiency contributes to impaired intrinsically photosensitive RGCs (ipRGCs) function, disrupted circadian entrainment, and neurodegeneration. Exogenous melatonin and analogues (e.g., 5-MCA-NAT, agomelatine) show promising IOP-lowering and neuroprotective effects in preclinical and early clinical studies. Novel delivery systems enhance ocular bioavailability and therapeutic efficacy. Melatonin plays a multifaceted role in glaucoma, influencing circadian rhythms, sleep quality, IOP regulation, and retinal neuroprotection. Its therapeutic potential warrants further investigation through controlled trials and optimized delivery strategies. Addressing circadian dysregulation may offer a novel avenue for comprehensive glaucoma management. Therefore, a structured narrative search was conducted in PubMed using the keywords "glaucoma" AND "melatonin", and findings were synthesized qualitatively due to methodological heterogeneity across clinical and preclinical studies.
