Drug delivery systems based on nanotechnology exhibit a number of advantages over traditional pharmacological formulations. Polymeric nanoparticles are commonly used as delivery systems and consist of synthetic or natural polymers that protect drugs from degradation in physiological environments. In this context, indolamine melatonin has been associated with several biological functions, including antioxidant, antitumor, immunoregulatory, neuroprotective, and cardioprotective effects. However, its availability, half-life, and absorption depend upon the route of administration, and this can limit its therapeutic potential. An alternative is the use of polymeric nanoparticle formulations associated with melatonin to increase its bioavailability and therapeutic dose at sites of interest. Thus, the objective of this review is to provide a general and concise approach to the therapeutic association between melatonin and polymeric nanoparticles applied to different biological disorders and to also highlight its advantages and potential applications compared to those of the typical drug formulations that are available.