Experiencing psychosocial adversities in early life such as maternal separation (MS) increases the risk of psychiatric disorders. Immune-inflammatory responses have imperative roles in the pathophysiology of psychiatric disorders. MS relatively changes the composition of intestinal microbiota leading to an overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and subsequently increases the corticosterone level. In this study, we aimed to evaluate the role of corticosterone in behavioral changes and microbiota modifications in a mouse model of MS afflicted neuroinflammatory response in the hippocampus. For this purpose, 180 min of MS stress was applied to mice at postnatal day (PND) 2-14 followed by behavioral tests including forced swimming test (FST), splash test, open field test (OFT) and elevated plus maze (EPM) at PND 50-52. For evaluating the role of corticosterone, mice were subjected to adrenalectomy. Using real-time RT-PCR, the expression of inflammatory genes was determined in the hippocampus and colon tissues. We found that MS provoked depressive- and anxiety-like behaviors in adult male mice. In addition, MS was able to active a neuroimmune response in the hippocampus, motivate inflammation and histopathologic changes in the colon tissue and modify the composition of gut microbiota as well. Interestingly, our findings showed that adrenalectomy (decline in the corticosterone level), could modulate the above-mentioned negative effects of MS. In conclusion, our results demonstrated that overactivation of HPA axis and the subsequent increased level of corticosterone could act, possibly, as the deleterious effects of MS on behavior, microbiota composition changes and activation of neuroimmune response.