Melatonin is a pleiotropic hormone with well-documented antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties, making it a promising candidate for the treatment of diverse diseases including neurodegenerative disorders, cardiovascular diseases, cancer, and sleep disturbances. However, its clinical translation has been hampered by several biopharmaceutical limitations, including poor aqueous solubility, extensive hepatic first-pass metabolism, rapid systemic clearance, and low oral bioavailability. Additionally, physiological barriers such as the blood-brain barrier, stratum corneum, and mucosal epithelia restrict its accumulation at target sites. In recent years, nanotechnology-based drug delivery systems have emerged as powerful tools to overcome these challenges. This review provides a comprehensive overview of advanced melatonin nanocarriers with a focus on their design principles, formulation strategies, and therapeutic applications. A central theme of this review is the integration of carrier design with biological barrier circumvention and administration routes-elucidating how specific nanocarrier platforms address the shortcomings of conventional immediate- and prolonged-release melatonin formulations through spatial and temporal control over drug distribution. We summarize recent preclinical progress in melatonin nanocarriers for a wide range of disease models, including Alzheimer's disease, Parkinson's disease, myocardial infarction, retinal degeneration and glaucoma, depression, and various cancers, with emphasis on the relationship between administration routes and therapeutic outcomes. Finally, critical challenges in clinical translation are addressed, including large-scale manufacturing, long-term toxicity evaluation, regulatory considerations, and the development of chronotherapy-compatible delivery systems. By integrating insights from materials science, pharmaceutics, and nanomedicine, this review aims to provide a rational framework for the future design and clinical application of melatonin-based nanotherapeutics.