Abstract: Xiao’er Guangpu Zhixie Oral Liquid (XeGp) is clinically used to treat pediatric diarrhea attributed to dampness encumbering the spleen, but its efficacy against bacterial diarrhea has not been fully established. In this study, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of XeGp against Salmonella Typhimurium SL1344 were determined using a microplate assay and a viable plate count method. A mouse model of bacterial diarrhea was also established to evaluate its antidiarrheal effects. The results showed that the MIC and MBC of XeGp against SL1344 corresponded to 1:20 and 1:10 dilutions, respectively. In an SL1344-induced mouse model of diarrhea, XeGp alleviated diarrhea symptoms, reduced the diarrhea index, attenuated diarrhea-associated body weight loss, and ameliorated intestinal histopathological damage caused by bacterial infection. These effects may be associated with reduced expression of TLR4 and phosphorylated NF-κB (p-NF-κB) in colonic tissues, increased expression of the tight junction proteins ZO-1 and occludin in intestinal tissues, and elevated secretory immunoglobulin A (sIgA) levels in the small intestinal mucosa. In addition, XeGp treatment had no significant effect on intestinal microbial diversity and partially restored the reductions in the total numbers of Lactobacillus and Bifidobacterium caused by Salmonella infection. When administered in combination with cefixime granules, XeGp enhanced, to some extent, the effects of cefixime granules in alleviating diarrhea, intestinal inflammation, and tissue injury caused by infection. It also partially ameliorated the intestinal microbiota dysbiosis induced by continuous cefixime treatment. In conclusion, XeGp has certain therapeutic effects on bacterial diarrhea caused by S. Typhimurium, providing a scientific basis for its clinical application.