Abstract: Xiao'er Guangpo Zhixie Koufuye is clinically used for pediatric diarrhea caused by dampness obstructing the spleen, but its efficacy against bacterial diarrhea has not been fully validated. In this study, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Xiao'er Guangpo Zhixie Koufuye against Salmonella typhimurium SL1344 were determined using the microplate method and plate colony counting method, and a mouse model of bacterial diarrhea was established to evaluate its antidiarrheal effects. Results showed that the MIC of Xiao'er Guangpo Zhixie Koufuye against SL1344 was at a 20-fold dilution concentration, and the MBC was at a 10-fold dilution concentration. In SL1344-induced mouse diarrhea model, Xiao'er Guangpo Zhixie Koufuye significantly improved diarrhea symptoms, reduced the diarrhea index, alleviated weight loss caused by diarrhea, and mitigated intestinal tissue damage caused by bacterial infection. These effects were associated with reduced expression levels of TLR4 and p-NF-κB but increased expression levels of tight junction proteins ZO-1 and Occludin in intestinal tissues, as well as elevated levels of sIgA in the small intestinal mucosa. Furthermore, treatment with Xiao'er Guangpo Zhixie Koufuye did not cause intestinal flora disturbance and could improve Salmonella infection-induced reduction of Lactobacillus and Bifidobacterium in diarrheal mice. When combined with cefixime granules, it significantly enhanced the efficacy of cefixime granules in improving diarrhea in mice, alleviated intestinal inflammation and damage caused by infection, and partially reversed the intestinal flora disturbance resulting from continuous treatment with cefixime granules. In summary, Xiao'er Guangpo Zhixie Koufuye demonstrates favorable therapeutic effects against bacterial diarrhea, providing a scientific basis for its clinical application.