Irinotecan is a well-known chemotherapy drug for the treatment of various cancers. However, delayed-onset diarrhea is a common adverse reaction, limiting the application of the drug. The study presented was designed to evaluate the preventive effects of Shengjiang Xiexin decoction (SXD) on irinotecan-induced diarrhea and to explore the possible mechanisms of this action. We established a diarrhea rat model. The condition of the rats was observed. The proliferation and apoptosis of intestinal cells were measured using immunohistochemical assays and a caspase-3 activity assay, respectively. The expression of Lgr5 and CD44 staining were used to observe intestinal stem cells (ISCs). In addition, the activity of -glucuronidase in the rats' feces was measured. Our results showed that the number of proliferating intestinal cells in the SXD groups was obviously higher, while the activity of caspase-3 was lower. The expression of Lgr5 and the integrated option density (IOD) of CD44 stain were increased significantly by SXD. Additionally, SXD decreased the activity of -glucuronidase after irinotecan administration. In conclusion, SXD exhibited preventive effects on irinotecan-induced diarrhea, and this action was associated with an inhibitory effect on intestinal apoptosis and -glucuronidase and a promotive effect on intestinal cell proliferation due to increased maintenance of ISCs.