Objective To investigate the immunoregulatory effect of P38 mitogen activated protease ( p38 MAPK) signals in rats with diarrhea-predominant irritable bowel syndrome (D-IBS). Methods Forty SPF Wistar rats (half male and half female) were randomly divided into a control group, and D-IBS model I (7 d), II (14 d) and III (21 d) groups, with 10 rats in each group. Rats in the model groups were developed through chronic restraint and senna decoction gavage, whereas the control rats were gavaged with the same volume of pure water. The D-IBS rates were killed on the seventh, fourteenth and twenty-first days, respectively. Rats in the control group were killed on the twenty-first day. The serum levels of IL-1β, IL-6 and TNF-α were measured by ELISA. The pathological changes in colon tissue were observed with hematoxylin and eosin (H&E) staining, and the p38 MAPK protein expression in the colon tissue was assessed with immunohistochemistry. Results Compared with the control group, the IL-1β, IL-6 and TNF-α levels in serum, and the p38 MAPK protein expression in colon tissue of the model groups were significantly higher ( P <0. 05, P <0. 01). The expression of p38 MAPK was positively correlated with IL-1β, IL-6 and TNF-α. Conclusions The D-IBS rat model, developed through chronic restraint and senna decoction gavage, may have upregulation of the expression of p38 MAPK, promoting the release of IL-1β, IL-6 and TNF-α, and inducing mild inflammation of the intestinal mucosa by activating the p38 MAPK signal pathway.