Objective The pathological mechanism of inflammatory bowel disease (IBD) is closely related to overactivation of the nuclear factor-κB ( NF-κB ) signaling pathway and M1 polarization of macrophages.Accordingly, this study aimed to investigate the effects of Kangfuxin solution on the regulatory mechanism of the NF-κB pathway during the progression of IBD. Methods A mouse model of IBD was established using dextran sodium sulfate (DSS). Forty-eight C57BL / 6 mice were divided into eight groups: Control, Model, SASP, KFX-L (5 mL / kg), KFX-M (10 mL / kg), KFX-H (20 mL / kg), NF-κBi-pretreated and NF-κBi-pretreated+KFX-H groups. The disease activity index (DAI), colonic mucosal damage index (CMDI), and histopathological scores were recorded. mRNA expression levels of CD86, tumor necrosis factor-α (TNF-α), phosphorylated NF-κB inhibitor α (p-IκBα),and interleukin ( IL)-1β in colonic tissues were detected by RT-qPCR, and protein expression levels of CD86,inducible nitric oxide synthase, and p-IκBα in colon tissues were detected by Western blot. Flow cytometry was used to analyze the effect of Kangfuxin liquid on the disease model. Results DSS-induction successfully established a mouse IBD model, with the measured values of various research indicators being highest in the Model group ( P<0. 05). The indicators in each group, except the SASP group, were significantly decreased compared with the Model group (P<0. 05), while downregulation of CD86 in the SASP group was not significant (P>0. 05). Among the three Kangfuxin liquid groups, the indicators were significantly reduced in the KFX-H group (P<0. 05). The combined intervention of NF-κB inhibitor and high-dose Kangfuxin liquid did not significantly enhance the therapeutic effect,with no significant differences in the measured values of each indicator compared with the single-drug groups ( P>0. 05). Conclusions Kangfuxin liquid, sulfasalazine and NF-κB inhibitors all have protective effects on colonic inflammation in DSS-induced IBD model mice, but their sites of action differ. Kangfuxin liquid and NF-κB inhibitors synergistically attenuate the intestinal inflammatory response by inhibiting NF-κB pathway activation through reducing IκBα phosphorylation, as well as down-regulating macrophage M1-type polarization. In contrast, sulfasalazine exerts a weaker effect on macrophage M1 polarization.