Neurodegeneration may be defined as a clinical condition wherein neurons gradually lose their structural integrity, viability, and functional abilities and the damage inflicted upon the neurons is often irreversible. The various mechanisms that have been observed to contribute to neurodegeneration include aggregation and accumulation of misfolded proteins, impaired autophagy, oxidative damage, neuroinflammation, mitochondrial defects, increased SUMOylation of proteins, impaired unfolded protein response (UPR) pathways, and disruption of axonal transport. Melatonin, a neurohormone, is involved in a variety of functions including scavenging free radicals, synchronizing the circadian rhythm, and mitigating immune response. Melatonin has shown to modulate the UPR pathway, antioxidant pathway through Nrf2 and inflammatory pathway through NFκB. The study aims to determine the efficacy of melatonin on neurodegeneration mediated by endoplasmic reticulum (ER) stress, inflammation, and oxidative damage through in silico approaches. The molecular targets chosen were ATF6, XBP1, PERK, Nrf2, and NFκB and they were docked against melatonin. Melatonin showed to have binding energy with ATF6 as - 4.8 kJ, with PERK as - 3.2 kJ, with XBP1 as - 4.8 kJ, with Nrf2 as - 4.5 kJ, and with that of NFκB as - 4.2 kJ, which implies it interacts well with them. Additionally various physiochemical analyses such as absorption, distribution, metabolism, excretion (ADME) were also carried out. Those analyses revealed that it has an optimal log P of about 1.98, optimal log S of - 2.34, is BBB permeant, has high GI absorption, is not a P-Gp substrate, has a TPSA of 54.12, has a molecular weight of 232.28, and has about 4 rotatable bonds. Also, it showed a bioactivity score of 0.06 for GPCR which implies that it is most likely to exert its function by binding GPCR. The findings imply that melatonin not only shows excellent interactions with the targets but also possesses drug-like physicochemical properties that makes it a valuable choice for the treatment of neurodegenerative disorders.