Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the purpose of anti-inflammation, antipyretic, and analgesia. For this aim, they are used for the alleviation of pain, fever, and inflammation associated with rheumatoid arthritis, sports injuries, and temporary pain. However, treatment with NSAIDs may be accompanied by adverse effects such as gastrointestinal damage and platelet dysfunction. As with the other NSAIDs, diclofenac sodium (sodium-(o-((2,6-dichlorophenyl)-amino)-phenyl)-acetate) (DS), an NSAID, has potent anti-inflammatory, analgesic, and antipyretic effects. However, treatment with DS may cause some adverse cerebral and cerebellar effects such as convulsions, disorientation, hallucination, and loss of consciousness. Melatonin (MLT) is a free-radical scavenger and possesses antioxidant properties. It has been reported to easily cross the blood-brain barrier, and is found in high concentrations in the brain after exogenous administration. It is also a neuroprotector in a wide range of conditions affecting the central nervous system CNS due to its free-radical scavenging activities and lipophilic-hydrophilic properties. Neuroprotective actions of MLT have been discovered in both in vitro and in vivo, and are a powerful scavenger of oxygen and nitrogen free radicals. Thus, MLT can protect the cell membrane, organelles, and core against free-radical damage. Therefore, it has been postulated that exogenous MLT acts as a neuroprotector contrary to DS neurotoxicity. In this review, we aimed to discuss the possible neuroprotective effects of MLT on DS toxicity.