Salmonella, an important zoonotic pathogen, causes significant morbidity and mortality in both humans and animals. Phloretin mainly isolated from strawberries and apples has the effects of treating inflammation and pathogenic bacteria, but its protective efficacy and mechanism of action against Salmonella spp. are less clear. In this study, we found that phloretin alleviated body weight loss, colon length shortening, and colonic pathological damage caused by S. Typhimurium. Phloretin also decreased S. Typhimurium translocation to the mesenteric lymph nodes (MLN) and spleen. Further mechanism studies showed that phloretin significantly inhibited inflammation and oxidative stress levels in the colonic tissue. Phloretin also prevented S. Typhimurium-mediated impairment in the colon epithelium barrier by the regulation ZO-1 and occludin levels. Interestingly, phloretin did not inhibit S. typhimurium growth in vitro, but reduced the internalization of S. Typhimurium into Caco-2 cells. Taken together, these findings indicated that phloretin may be a new dietary strategy to combat the disease.