Objective Based on the close association between the pathological mechanism of inflammatory bowel disease (IBD) and the overactivation of the nuclear factor κB (NF-κB) signaling pathway and M1 polarization of macrophages, this study uses Kangfuxin Solution to conduct a comparative study exploring the regulatory mechanism of the NF-κB pathway during the progression of IBD. Methods A mouse model of inflammatory bowel disease (IBD) was established by inducing with dextran sodium sulfate (DSS). Forty-eight C57BL/6 mice were divided into eight groups: the control group, the model group, the sulfasalazine group (SASP), different-dose Kangfuxin Liquid groups (5, 10, 20 mL/kg), the NF-κB inhibitor pretreatment group, and the NF-κB inhibitor pretreatment + KFX-H group. The disease activity index (DAI), colonic mucosal damage index (CMDI), histopathological scores were recorded, the mRNA expression levels of CD86, tumor necrosis factor-α (TNF-α), phosphorylated IκBα (p-IκBα) and IL-1β in colonic tissues were detected by fluorescence quantitative PCR, and protein expression levels of CD86, iNOS, and phosphorylated IκBα (p-IκBα) in colon tissues by protein blotting (Western Blot). Flow cytometry was used to analyze the effect of Kangfuxin liquid on the disease model. The detection results were compared and analyzed among groups. Results The DSS-induced method successfully established a mouse IBD model, with the measured values of various research indicators being the highest in the model group (P<0.05). After drug intervention, except for the sulfasalazine group in which the downregulation of CD86 was relatively small and the difference compared with the model group was not statistically significant (P>0.05), the indicators in each group were significantly decreased compared with those in the model group (P<0.05). Among the three groups intervened with Kangfuxin Liquid, the high-dose group showed a significant downregulation of indicators (P<0.05). However, the combined intervention of NF-κB inhibitor and high-dose Kangfuxin Liquid did not significantly enhance the therapeutic effect, and the differences in the measured values of each indicator compared with those in the groups with single-drug intervention were not statistically significant (P>0.05). Conclusion NF-κB inhibitors, sulfasalazine, and Kangfuxin liquid all have protective effects on colonic inflammation in DSS-induced IBD model mice, but their sites of action differ. NF-κB inhibitors and Kangfuxin liquid are synergistic in attenuating the intestinal inflammatory response by inhibiting NF-κB pathway activation through lowering the level of IκBα phosphorylation, as well as down-regulating macrophage M1-type polarization.