Abstract Background and Purpose: Microglia-mediated neuroinflammation contributes to major depressive disorder (MDD). Targeting microglia is a promising strategy for treating MDD. Patchouli alcohol (PA), a active component of Pogostemon cablin, has anti-inflammatory and neuroprotective effects. Here, we investigate the microglia-mediated neurogenesis pathway in which PA ameliorates depressive-like behaviors in stress-induced animal model of depression. Experimental Approach: C57BL/6 male mice were exposed to chronic mild stress (CMS) for 4 weeks, then administered PA intraperitoneally at 10, 20 or 40 mg/kg once per day for 3 weeks. The antidepressant effects of PA were evaluated in the sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes and activation of the NLRP3 inflammation were analyzed using RT-PCR, western blotting and immunofluorescence staining. Effects of PA on neurogenesis were analyzed in vitro and in vivo using immunofluorescence staining. Key Results: Behavioral assessments showed that PA alleviated depressive-like behaviors in CMS-exposed mice. CMS induced microglial activation and pro-inflammatory profiles, which were blocked by PA treatment. PA attenuated the activation of NLRP3 inflammasome, leading to decreases in the levels of caspase-1, ASC, IL-1β, and IL-18 in the hippocampus of CMS-exposed mice. In primary microglia cultures, PA inhibited LPS-induced NLRP3 inflammasome activation. PA rescued inflammation-inhibited neurogenesis in vivo and in vitro. Conclusion and implications: Our results suggest that PA inhibits the NLRP3 inflammasome and promotes microglia-mediated neurogenesis, leading to antidepressant effects. Thus, PA may be a novel treatment for inflammation-driven mental disorders.