Objective To establish a C57BL/6 mouse model of intestinal infection induced by S. Typhimurium. Methods In order to improve the infectious sensitivity of S. Typhimurium, C57BL/6 mice were intragastrically given 5% (w/v) NaHCO_3. Then mice were challenged with S. Typhimurium. The health condition, survival and body weight of mice were observed from day 0 to day 7 after the bacterial infection. The pathological changes were also examined. Results the mice challenged with S. Typhimurium showed decreased body weight and typical clinical signs, including in appetence, piloerection and low survival rate. Macroscopic dissection revealed that intestinal hyperemia and swelling were founded in the mice challenged with S. Typhimurium. Histopathology showed intestinal epithelial and mucosal damages. Conclusions We have successfully established a C57BL/6 mouse model of S. Typhimurium infection. This model may be of crucial significance for studying the biological functions of associated immunological molecules or cytokines in the process of inflammatory bowel disease induced by S. Typhimurium.