The effects of compound Sophorae Flavescentis Jiechangrong capsule (CSFJC) on the expression of nuclear factor-κB p65 (NF-κB p65) and signal transducer and activator of transcription 6 (STAT6) in the intestinal mucosa of patients with ulcerative colitis and the possible mechanism were investigated. Eighteen patients with ulcerative colitis were randomly divided into a traditional Chinese medicine (TCM) group ( = 11) treated by CSFJC and a western medicine (WM) group ( = 7) treated by Sulfasalazine tablets. The treatment duration lasted eight weeks. Before and after the treatment, the symptoms and the physical signs were observed, and the routine stool test, the colonoscopy, and pathological examination were performed in the two groups. The expression levels of NF-κBp65 and STAT6 were detected by using immunohistochemistry. The results showed that the total effective rate of the curative effectiveness in TCM and WM groups was 100% and 71.4%, respectively, and the total effective rate of colonic mucosa lesion in TCM and WM groups was 90.9% and 71.4%, respectively, with the differences being significant (all < 0.05). The total effective rate of syndromes of damp-heat blocking according to the TCM in TCM and WM groups was 90.9% and 71.4%, respectively. After the treatment, the expression of NF-κB p65 and STAT6 in the two groups was decreased, and the decrease of NF-κB p65 and STAT6 expression in TCM group was more significant than in WM group ( < 0.05). It was concluded that CSFJC can inhibit the activation and expression of NF-κB p65 and STAT6 in the intestinal mucosa of patients with ulcerative colitis, which is a possible mechanism for CSFJC treating ulcerative colitis.