Neurodegenerative diseases are typified by neuronal loss associated with progressive dysfunction and clinical presentation. Neurodegenerative diseases are characterized by the intra- and extracellular conglomeration of misfolded proteins that occur because of abnormal protein dynamics and genetic manipulations; these trigger processes of cell death in these disorders. The disrupted signaling mechanisms involved are oxidative stress-mediated mitochondrial and calcium signaling deregulation, alterations in immune and inflammatory signaling, disruption of autophagic integrity, proteostasis dysfunction, and anomalies in the insulin, Notch, and Wnt/β-catenin signaling pathways. Herein, we accentuate some of the contemporary translational approaches made in characterizing the underlying mechanisms of neurodegeneration. Melatonin-induced cognitive enhancement and inhibition of oxidative signaling substantiates the efficacy of melatonin in combating neurodegenerative processes. Our review considers in detail the possible roles of melatonin in understanding the synergistic pathogenic mechanisms between aggregated proteins and in regulating, modulating, and preventing the altered signaling mechanisms discovered in cellular and animal models along with clinical evaluations pertaining to neurodegeneration. Furthermore, this review showcases the therapeutic potential of melatonin in preventing and treating neurodegenerative diseases with optimum prognosis.