Macranthol is a lignans natural product isolated from Illicium dunnianum Tutch. Our previous studies have shown that BDNF dependent signaling pathway activation was involved in the antidepressant-like effects of macranthol. However, it is not clear whether neuro-inflammation suppression is involved in the effects of macranthol. Therefore, the aim of this present study was to determine whether macranthol affected the neuro-inflammation system in lipopolysaccharide (LPS)-induced mice by measuring pro-inflammatory cytokines and CD11b. Macranthol was orally administrated for successive seven days before a single LPS injection. The behavioral evaluation showed that macranthol prevented LPS-induced depressive-like deficits both in sucrose preference test and forced swimming test. The elevation of serum and prefrontal cortex pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was decreased by macranthol pretreatment. In addition, LPS induced the elevation of CD11b in the prefrontal cortex, which was also inhibited by macranthol. Last but not the least, the immunofluorescence found that the number of positive iba-1 cells was also decreased by macranthol. These findings suggest that macranthol could alleviate depressive-like behaviors in mice induced by LPS that are mediated, at least by suppressing microglia-related neuro-inflammation in the prefrontal cortex.