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Chronic social isolation stress (SIS) could impair learning and memory-related behaviors. Herein, we investigated the efficacy of Melatonin in treatment of memory despair and also its possible underlying mechanism of action in an animal model of SIS. For this purpose, mice were allocated to two opposing conditions, including social condition (SC) and isolated condition (IC), for five weeks. The study consisted of three groups, including saline-treated SC, saline-treated IC, Melatonin-treated IC (10 mg/kg/day for five successive days). At the end of the isolation period, mice underwent three neurobehavioral tests: passive avoidance (PA), Morris water maze (MWM), and Y maze (YM) tests. Hippocampus samples were obtained and the expressions of BDNF, TrkB, phosphorylated TrkB (pTrkB), CREB, phosphorylated CREB (pCREB), as well as M1 and M2 microglia were assessed. Interpreting the behavioral tests, we found that isolated mice showed lower freezing response in the PA test, lower number of novel arm visits in the YM, and higher escape latency and less time spent in the target quadrant in the MWM, when compared to SC rodents (P values < 0.001). The isolated group had higher M1/M2 relative ratio (P < 0.001), as well as lower concentrations of BDNF mRNA (p < 0.001) and protein (P < 0.001), TrkB protein (P = 0.035), CREB mRNA (P < 0.001) and protein (P = 0.012), pTrkB (P < 0.001), and pCREB (P = 0.035). However, Melatonin relatively reversed the behavioral, cellular, and molecular effects of SIS. Taken together, melatonin therapy could alleviate memory impairment through switching microglial polarization from M1 to M2 phenotype along with altered expression and function in the BDNF/TrkB/CREB signaling pathway. Animals with chronic social isolation stress show significant impairment in various domains of learning and memory. As depicted in the graph, however, this impairment could be reversed by melatonin therapy. One of the major melatonin mechanisms of action appears to be through BDNF/TrkB/CREB signaling pathway, where its administration could restore the reduced levels and function of the pathway components. Beyond that, the graph suggests the prominent effect of melatonin on M1 and M2 microglia polarization as a possible explanation for its impact on the BDNF signaling. In other words, the elevation in the expression level of M2 microglia along with the reduction of M1 microglia results in higher secretion of M2-derived BDNF. This could lead to the activation of intraneuronal cascades, which finally gives rise to the promotion in the level of Neuron-derived BDNF as a neuroprotective factor. [Display omitted] [ABSTRACT FROM AUTHOR]