Saikosaponin-d (SSd), a triterpenoid saponins compound extracted from Radix Bupleuri, has been demonstrated to effectively alleviate chronic mild stress-induced depressive behaviors in rats, but the underlying molecular mechanisms are still uncertain. Increasing evidence indicated that microglia activation and inflammatory responses were involved in the pathogenesis of depression. Thus, we desired to induce inflammation-related depressive-like behaviors in mice by injecting lipopolysaccharide (LPS) to investigate whether the antidepressant effect of SSd is related to inhibiting inflammation. The results of behavioral tests showed that SSd administration ameliorated LPS-induced depressive-like behaviors, as shown by increased sucrose consumption in the sucrose preference test and decreased immobility time in the tail suspension test and forced swimming test. Furthermore, immunostaining results showed that SSd pretreatment inhibited LPS-induced microglia activation in the hippocampus of mice and primary microglia cells. Enzyme-linked immunosorbent assay (ELISA) results showed that SSd pretreatment suppressed LPS-induced overexpression of inflammatory factors such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α both in vivo and in vitro. Immunostaining and western blot analysis results demonstrated that SSd pretreatment also inhibited LPS-induced HMGB1 translocation from nuclear to extracellular and decreased the protein levels of TLR4, p-IκB-α, NF-κBp65. These results suggested that SSd effectively improved LPS-induced inflammation-related depressive-like behaviors by inhibiting LPS-induced microglia activation and neuroinflammation, and the possible mechanism might associate with the regulation of the HMGB1/TLR4/NF-κB signaling pathway.