Abstract：Objective：To observe the clinical efficacy of modified Xiaoyao San combined with Paroxetine in the treatment of post-stroke depression （PSD） with liver stagnation and spleen deficiency syndrome. Methods：A total of 102 PSD patients with liver stagnation and spleen deficiency syndrome admitted to Wenzhou TCM Hospital of Zhejiang Chinese Medical University from January to December 2023 were selected and divided into the combination group and the control group using the random number table method，with 51 cases in each group. Ultimately，49 cases in each group completed the study. Both groups received conventional secondary prevention treatment for stroke such as antiplatelet aggregation， blood lipid regulation， and blood pressure control. The control group additionally received Paroxetine Hydrochloride Enteric-Coated Sustained-Release Tablets， while the combination group received modified Xiaoyao San in addition to the control group's treatment. Both groups were treated for eight weeks. The clinical efficacy， incidence of adverse reactions， as well as traditional Chinese medicine syndrome scores， Hamilton Depression Scale （HAMD） scores，Self-Rating Depression Scale （SDS） scores，Pittsburgh Sleep Quality Index （PSQI） scores， inflammatory factor levels [interleukin （IL）-1β， IL-6， and tumor necrosis factor- α （TNF- α）]， gut microbiota diversity indices （Shannon index，Observed species index，and Chao 1 index）， and the abundance of gut microbiota （Bifidobacterium，Lactobacillus，Enterococcus，Escherichia coli） before and after treatment were compared between the two groups. Results：After treatment，the total effective rate in the combination group was 91.84% （45/ 49）， which was higher than 73.47% （36/49） in the control group （P＜0.05）. The scores of main and secondary traditional Chinese medicine symptoms， HAMD， SDS， and PSQI， and the levels of IL-1β， IL-6， and TNF-α decreased in both groups compared with those before treatment （P＜0.05）， and these scores and levels in the combination group were lower than those in the control group （P＜0.05）. The Shannon index，Observed species index， and Chao1 index increased in both groups compared with those before treatment （P＜0.05），and these indices in the combination group were higher than those in the control group （P＜0.05）. The abundances of Bifidobacterium and Lactobacillus increased in both groups compared with those before treatment （P＜0.05）， and were higher in the combination group than in the control group （P＜0.05）. The abundances of Enterococcus and Escherichia coli decreased in both groups compared with those before treatment （P＜0.05），and were lower in the combination group than in the control group （P＜0.05）. There was no statistically significant difference in the incidence of adverse reactions between the two groups （P＞0.05）. Conclusion：The application of modified Xiaoyao San combined with Paroxetine has good effect in the treatment of PSD with liver depression and spleen deficiency syndrome， which can improve the curative effect， effectively reduce depression， relieve related symptoms， improve sleep quality， reduce inflammatory reactions，maintain intestinal flora homeostasis，and has good safety.