Melatonin is a pleiotropic molecule that, after a short-term sleep deprivation, promotes the proliferation of neural stem cells in the adult hippocampus. However, this effect has not been observed in long-term sleep deprivation. The precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated, but evidence indicates that epigenetic regulators may be involved in this process. In this study, we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword clusterization. Our results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate gyrus. We observed that let-7b, mir-132, and mir-124 were highly expressed in the dentate gyrus after melatonin administration, but they were not modified by sleep deprivation. In addition, we found more Sox2+/5-bromo-2′-deoxyuridine (BrdU)+ cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the un-treated group. These findings may support the notion that melatonin modifies the expression of epigenetic mediators that, in t, regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived conditions. All procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara, Mexico (approval No. CI-16610) on January 2, 2016.