Abnormal activation of nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome could induce inflammation in the central nervous system and result in the hyperactivity of HPA axis, which were involved in the pathophysiology of depression. Baicalin, a major polyphenol compound extracts from Scutellaria radix roots, has been previously confirmed to normalize the hyperactivity of HPA axis in rats received chronic mild stress. However, its antidepressant effects and mechanisms are remains unclear in chronic unpredictable mild stress (CUMS) model of depression. In this study, CUMS treated rats showed a notable depressive-like behavior (decreased sucrose intake and locomotor activity, and increased immobility time), and significant increase in the activation of NLRP3 inflammasome and the levels of pro-inflammatory cytokines (IL-1β and IL-6) in rat prefrontal cortex. Treatment with baicalin (20, 40 mg/kg) significantly reversed these changes. The present study confirmed that baicalin has antidepressant effect and its mechanisms likely related to the inhibition of NLRP3 inflammasome activation in rat prefrontal cortex.