Background <p>The global incidence of ulcerative colitis (UC) is increasing, yet effective clinical treatment options remain limited. Qinlian Yuyang Decoction (QYD), a modified formulation based on Gegen Qinlian Decoction (GQD), has been optimized to better alleviate the pathological characteristics of UC. Although QYD is considered potentially more suitable for UC treatment, its potential mechanism of action is still unclear.</p> Purpose <p>To explore the mechanism of QYD in the treatment of UC based on multi-omics.</p> Method <p>The therapeutic effects of QYD for UC were evaluated using the dextran sulfate sodium (DSS)-induced UC mice model. Then, 16S rRNA sequencing and untargeted metabolomics were employed to identify key microbiota and metabolites regulating the intestinal microenvironment. Furthermore, proteomic analysis was carried out to elucidate the underlying mechanisms mediated by the key metabolites.</p> Results <p>QYD alleviated physiochemical indices in UC mice, including weight loss, diarrhea, and bloody stools, resulting in lower Disease Activity Index (DAI) scores. It also suppressed inflammatory and intestinal barrier disruption in colonic tissues. Integrated metabolomic and 16S rRNA analyses demonstrated that the therapeutic effects of QYD on UC are mediated through enrichment of gut commensal <i>D. longicatena</i> and increasing tyrosine levels. Oral treatment of live <i>D. longicatena</i> considerably ameliorates colitis symptoms in UC mice. Tyrosine has similar protective effects against UC. Our investigation using quantitative proteomics to elucidate the mechanism of tyrosine in UC revealed that tyrosine suppresses inflammatory signaling pathways, modulates immune responses, and inhibits vascular endothelial cell migration and proliferation in the UC model—effects consistent with those of QYD. In summary, our findings indicate that QYD alleviates UC by elevating gut levels of the commensal bacterium <i>D. longicatena</i> and tyrosine, thereby suppressing inflammatory and immune responses while protecting the intestinal barrier. These results identify novel therapeutic targets and provide fresh perspectives for UC treatment.</p> Conclusion <p>These findings suggest that <i>Dorea longicatena</i> and tyrosine play indispensable roles in the therapeutic mechanism of QYD against UC.</p> Graphical Abstract <p></p>