Irinotecan (CPT‐11) is used for therapy of various cancers. However, it has several serious adverse reactions such as diarrhea which is caused by SN‐38, the active form of CPT‐11. This study aimed to evaluate the effectiveness of Jiawei xianglian decoction (JWXLD), which has been widely used for the treatment of diarrhea in China. In this study, a mouse model with delayed diarrhea was generated by CPT‐11. Real‐time PCR and enzyme‐linked immunosorbent assay (ELISA) were performed to explore intestinal microflora and inflammatory cytokine. Hematoxylin and eosin (H&E) staining was used to analyze tissue morphology. We found that 0.12, 0.23, and 0.46 g JWXLD significantly reduced the severity of CPT‐11‐induced diarrhea. The levels of Lactobacillus (Lacto) and Bifidobacterium (Bifid) were significantly downregulated by CPT‐11, and these effects can be reversed by JWXLD treatment. Furthermore, JWXLD was observed to decrease the activity of β‐glucuronidase (β‐GD). Histopathological data showed that CPT‐11 induced severe intestinal mucosal injury, which was characterized as grade 6, and JWXLD significantly alleviated the injury. In addition, CPT‐11 increased the productions of tumor necrosis factor‐alpha (TNF‐α), tumor necrosis factor‐beta (TNF‐β), interleukin‐6 (IL‐6), and interleukin‐1 (IL‐1), but decreased interleukin‐15 (IL‐15), interleukin‐7 (IL‐7), and uridine diphosphate‐glucuronosyltransferase 1A1 (UGT1A1). In conclusion, JWXLD can counteract these effects caused by CPT‐11 treatment. JWXLD could alleviate CPT‐11‐induced diarrhea.