BACKGROUND: A high-fat diet (HFD)-induced obesity/hyperlipidemia is accompanied by hormonal and neurochemical changes that can be associated with depression. Emerging studies indicate that simvastatin (SMV, decreasing cholesterol levels) has therapeutic effects on neurological and neuropsychiatric diseases through hippocampal-dependent function. However, the studies on the HFD exposure in adolescent animals, which investigate the neuroprotective effects of SMV on the hippocampal morphology, serotonin (5-HT) system and inflammation, are limited. Hence, the aim of this study was to determine whether SMV attenuates HFD-induced major depressive disorders in adolescent animals and, more specifically, acts as an anti-neuroinflammatory response. METHODS: Twenty-four male C57BL/6 mice were fed a control (n = 8), HFD (n = 8) and HFD + SMV (n = 8) for 14 weeks. In HFD + SMV group, SMV (10 mg/kg) was administrated from the 10th week of HFD feeding. The open field test (OFT) and the tail suspension test (TST) were used to examine the effect of SMV on behavioral performance. HE and Nissl staining were conducted to detect hippocampal morphology and neural survival. Expression of the inflammatory cytokine genes was assayed by quantitative polymerase chain reaction (Q-PCR). RESULTS: Firstly, alterations in lipid parameters were minimized after SMV treatment. HFD-induced depression-like behavior, which was evidenced by an increase in immobility time in TST along with considerable decrease in locomotion activity, was significantly attenuated by SMV therapy for 4 weeks. Additionally, SMV could reduce HFD-induced structural abnormality, neuronal injury, serotonergic system disturbance and pro-inflammatory cytokine over-expression in the hippocampus. Neuroimmunological changes in central hippocampus displayed a similar characteristic (only IL-1β, IL-6, TNF-α) with that in periphery spleen, whereas they appeared in an entirely opposite trend with that in cerebral cortex. CONCLUSION: Our results suggest that SMV may be a promising treatment for HFD-induced depression-like behavior during adolescent period through brain region-specific neuroninflammatory mechanisms.