Depression is the disease of the modern era. The lack of response to the available antidepressants, which were developed on the basis of the monoaminergic deficit hypothesis of depression, has encouraged scientists to think about new mechanisms explaining the pathogenesis of depression. In this context, the inflammatory theory has emerged to clarify many aspects of depression that the previous theories have failed to explain. Toll-like receptor-4 (TLR-4) has a regulatory role in the brain's immune response to stress, and its activation is suggested to play a pivotal role in the pathophysiology of depression. In this study, we tested eritoran (ERI), a TLR-4 receptor-4 antagonist, as a potential antidepressant. We investigated the effect of long-term administration of ERI in three different doses on behavioral changes, hippocampal and prefrontal cortex (PFC) neurogenesis, and γ-aminobutyric acid (GABA)/glutamate balance in male Wistar rats exposed to chronic restraint stress (CRS). Long-term administration of ERI ameliorated CRS-induced depressivelike symptoms and hypothalamic–pituitary–adrenal axis hyperactivity alongside reducing levels of hippocampal and PFC inflammatory cytokines, restoring GABA and glutamate balance, and enhancing PFC and hippocampal neurogenesis, by increasing BDNF gene and protein expression in a dose-dependent manner. The resultsm demonstrate an antidepressant-like activity of ERI in Wistar rats exposed to CRS, which may be largely mediated by its ability to reduce neuroinflammation, increase BDNF, and restore GABA/glutamate balance in prefrontal cortex and hippocampus. Nonetheless, further studies are needed to characterize the mechanism of the antidepressant effect of ERI. Behavioural Pharmacology 00:000–000 Copyright ©2018 Wolters Kluwer Health, Inc. All rights reserved.