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Spinal cord injury (SCI) from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.