Neuroinflammation, oxidative stress and apoptosis are implicated in the pathogenesis of neuropsychiatric diseases like anxiety and depression. 25-Methoxyhispidol A (25-MHA) is a triterpenoid isolated from the immature fruit of Poncirus trifoliate. Recently, its crude extracts have been shown to exhibit anti-bacterial and anti-inflammatory activities. The current study investigated the effect of 25-MHA (1, 5 and 10 mg/kg) against bacteria-induced anxiety and depression-like behaviors in mice. Mice were challenged intraperitoneally (i.p.) with LPS (0.83 mg/kg), S. aureus and E. coli after 30 min of 25-MHA treatment. 25-MHA (10 mg/kg) significantly mitigated the anxiety-like behavior as indicated by the results of elevated plus maze test, open field test, and light-dark box test. It also demonstrated the anti-depressant like effect by significantly reducing the immobility time in tail suspension test and forced swim test. The oxidative stress was reduced by pretreatment with 25-MHA, improving the antioxidant enzymes level such as glutathione, glutathione sulfo-transferase, and catalase. Similarly, 25-MHA attenuated the bacterial infection induced neuroinflammation by inhibiting the interleukin- 6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α) levels in prefrontal cortex and hippocampus regions. Pretreatment of 25-MHA also decreased the cortisol level and prevented changes in the thickness of the granular layer in the dentate gyrus. It also inhibited the DNA damage in hippocampus region as analyzed by comet assay. Hence, present results demonstrated that 25-MHA possesses anti-anxiety and anti-depressant activities due to the ability to reduce neuroinflammatory, oxidative stress and apoptosis induced by the administration of LPS, E. coli, and S. aureus.