OBJECTIVES: This investigation aimed to evaluate the efficacy, key active ingredients, and mechanisms of Zuoqing San (ZQS), a traditional Chinese medicine formula, in managing sigmoid ulcerative colitis (SUC). METHODS: A cohort of 126 participants was recruited and treated with ZQS at a daily dosage of 100 mL for 12 weeks. The primary endpoint was the percentage of subjects achieving favorable treatment outcomes. Liquid chromatography-mass spectrometry was employed to identify the principal ingredients of ZQS. Network pharmacology was utilized to predict the central targets of its active ingredients. Protein-protein interaction networks, Gene Ontology enrichment analyses, and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted for identified core targets. Finally, molecular dynamics simulations of key active ingredients and core targets were performed. RESULTS: Following 12 weeks of therapy, with a withdrawal rate of 7.93 %, favorable treatment outcomes were observed in 31.03 % of subjects at 4 weeks, 66.37 % at 8 weeks (Odds Ratio: 1.54, 95 % Confidence Interval: 0.41-1.83), and 68.10 % at 12 weeks (Odds Ratio: 1.86, 95 % CI: 0.32-1.27). ZQS comprises 31 principal chemical constituents. Key targets within the protein-protein interaction network included TNF, AKT1, IL6, IL1beta, PTGS2, TP53, JUN, MMP9, CASP3, HIF1A, and BCL1. Pathway analysis indicated ZQS primarily impacts the TNF, NF-kB, and IL-17 signaling pathways. Molecular dynamics simulation results showed oxymatrine, cynarin had higher affinity with TNF and IL1beta, respectively. CONCLUSIONS: This research elucidates the active components of ZQS and its potential multicomponent-multitarget-multipathway pharmacological mechanisms, demonstrating promising therapeutic potential for SUC management.