Depression, a prevalent and multifaceted mental disorder, has emerged as a significant public health concern due to its escalating prevalence and heightened risk of severe suicidality. Given its profound impact, the imperative for preventing and intervening in depression is paramount. Substantial evidence underscores intricate connections between depression and cardiovascular health. SheXiangXinTongNing (XTN), a recognized traditional Chinese medicine for treating Coronary Heart Disease (CHD), prompted our exploration into its antidepressant effects and underlying mechanisms. In this investigation, we assessed XTN's antidepressant potential using the chronic unpredictable mild stress (CUMS) mice model and behavioral tests. Employing network pharmacology, we delved into the intricate mechanisms at play. We characterized the microbial composition and function in CUMS mice, both with and without XTN treatment, utilizing 16S rRNA sequencing and metabolomics analysis. The joint analysis of these results via Cytoscape identified pivotal metabolic pathways. In the realm of network pharmacology, XTN administration exhibited antidepressant effects by modulating pathways such as IL-17, neuroactive ligand-receptor interaction, PI3K-Akt, cAMP, calcium, and dopamine synapse signaling pathways. Our findings revealed that XTN significantly mitigated depression-like symptoms and cognitive deficits in CUMS mice by inhibiting neuroinflammation and pyroptosis. Furthermore, 16S rRNA sequencing unveiled that XTN increased the alpha-diversity and beta-diversity of the gut microbiome in CUMS mice. Metabolomics analysis identified brain metabolites crucial for distinguishing between the CUMS and CUMS+XTN groups, with a focus on pathways like Tryptophan metabolism and Linoleic acid metabolism. Notably, specific bacterial families, including Alloprevotella, Helicobacter, Allobaculum, and Clostridia, exhibited robust co-occurring relationships with brain tryptophan metabolomics, hinting at the potential mediating role of gut microbiome alterations and metabolites in the efficacy of XTN treatment. In conclusion, our study unveils modifications in microbial compositions and metabolic functions may be pivotal in understanding the response to XTN treatment, offering novel insights into the mechanisms underpinning the efficacy of antidepressants.