Schisandrin B (Scheme B) is the most abundant and active lignan monomer isolated from Schisandra chinensis. At present, most reports focus on its cardioprotective and hepatoprotective effects, however, the related reports on gastrointestinal protective effects are still limited. The study aims to evaluate the protective effect of Scheme B on cisplatin‐induced rat intestinal crypt epithelial (IEC‐6) cell injury and the possible molecular mechanisms. The results showed that Scheme B at 2.5, 5 and 10 μM could inhibit dose‐dependently the reduction of cell activity induced by cisplatin exposure at 1 μM, decrease the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) to alleviate oxidative stress injury in IEC‐6 cell lines. Meanwhile, Scheme B could relieve cisplatin‐induced apoptosis by regulating PI3K/AKT and the downstream caspase signaling pathway. The results from flow cytometry analysis and mitochondrial membrane potential (MMP) staining also demonstrated the anti‐apoptosis effect of Scheme B. Furthermore, Scheme B was found to reduce the inflammation associated with cell damage by evaluating the protein expressions of the nuclear factor‐kappa B (NF‐κB) signaling pathway. Importantly, Wnt/β‐catenin, as a functional signaling pathway that drives intestinal self‐recovery, was also in part regulated by Scheme B. In conclusion, Scheme B might alleviate cisplatin‐induced IEC‐6 cell damage by inhibiting oxidative stress, apoptosis, inflammation, and repairing intestinal barrier function. The present research provides a strong evidence that Scheme B may be a useful modulator in cisplatin‐induced intestinal toxicity.