Objective ·To investigate the effect of Th17 cell-specific Stat3 knockout on anxiety- and depressive-like behaviors. Methods ·Mice with specific Stat3 knockout in Th17 cells (Stat3^fl/fl; Il17a-CreERT2), named Stat3^△Il17a , and wild-type mice (Stat3^fl/fl, WT) were generated through the Cre/LoxP system, and Stat3 knockout was induced by intraperitoneal injection of tamoxifen. CD4⁺T cells were isolated using magnetic-activated cell sorting and induced to differentiate into Th17 cells. Reverse transcription polymerase chain reaction and Western blotting were used to verify Stat3 knockout efficiency. Mice were assigned into 4 groups: WT-C group, Stat3^△Il17a -C group, WT-P group, and Stat3^△Il17a -P group. The periodontitis model was established in the WT-P group and the Stat3^△Il17a -P group by injection of Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) into the gingival sulcus. Behavioral tests, including the open field test, elevated zero maze, and forced swimming test, were conducted to evaluate changes in anxiety- and depressive-like behaviors. Micro-computed tomography was used to observe destruction of alveolar bone. Neuronal injury was observed by H-E staining, and the level of brain-derived neurotrophic factor (BDNF) was detected by enzyme-linked immunosorbent assay. Results ·mRNA expression and protein levels of Stat3 in Stat3^△Il17a mice were inhibited compared to WT mice (P<0.05). Experimental periodontitis model was successfully established in the WT-P group and the Stat3^△Il17a -P group. The degree of alveolar bone destruction was reduced in the Stat3^△Il17a -P group compared to the WT-P group. In the WT-P group, decreased residence time in the central area and in the open area was observed in the open field test and elevated zero maze respectively, and increased immortal time was recorded in the forced swimming test (P<0.05). Moreover, neuronal injury was detected and significantly decreased expression levels of BDNF in the brain were measured in the WT-P group compared with the WT-C group (P<0.05). The degree of abnormal behaviors and neuronal injury was reduced in the Stat3^△Il17a -P group compared to the WT-P group (P<0.05). Moreover, the level of BDNF in the Stat3^△Il17a -P was higher than that in the WT-P group (P<0.05). Conclusion ·Periodontitis may contribute to anxiety- and depressive-like behaviors and neuronal damage in mice, while Th17-specific conditional knockout of Stat3 could significantly alleviate pathological behaviors and neuronal damage. Stat3-mediated-Th17 cell immune responses may play a crucial role in the correlation between periodontitis and anxiety and depression.