Objective: To explore the protective effect of sodium tanshinone II A sulfonate (STS) on small intestine injury in rats with sepsis and its possible mechanism. Methods: According to a random number table, 24 Tats were randomly divided into 3 groups: sham operation group (sham group), sepsis model group (model group) and STS treatment group (STS group), with 8 Tats in each group. A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 5 h. STS (1 mg/kg) was slowly injected through the right external jugular vein after CLP. The histopathologic changes in the intestine tissue were observed under a light microscope, and the intestinal epithelial cell apoptosis was evaluated by terminal deoxynucleoddyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. The expressions of Bcl-2, Bax and nuclear factor kappa B (NF-kappa B) p65 in the intestinal tissue was determined by Western blot. The levels of tumor necrosis factor alpha (INF-alpha) and interleukin 6 (IL-6) in the intestinal tissue were determined using enzyme-linked immuno-sorbent assay (ELISA). Results: Obvious injuries were observed in the intestinal tissue in the CLP group compared with the sham group. The expression of NF-kappa B p65 and the levels of TNF-alpha and IL-6 were up-regulated after CLP, the apoptosis of intestinal epithelial cells was increased after CLP, and the ratio of Bcl-2 to Bax was decreased. STS post-treatment could attenuate the injury on the intestinal tissue induced by CLP, decrease the apoptosis of intestinal epithelial cells and the levels of NF-kappa B p65, TNF-alpha and IL-6, and increase the ratio of Bcl-2 to Bax. Conclusion: STS can protect the small intestine in rats with sepsis, and the mechanism may be associated with the inhibition of intestinal epithelial apoptosis and the reduction of activation of inflammatory cytokines.