Oxypeucedanin (OPD) is a compound naturally present in plants such as Peucedanum praeruptorum, a kind of medicinal herb which displays anti-inflammatory activities. However, its protective role on chemotherapy-induced inflammatory injuries has not been well studied. In the present study, we found that OPD could alleviate cisplatin (CDDP)-induced intestinal inflammatory injury in mice, which was accompanied by the decrease of immune cell infiltration and reverse of mitochondrial dysfunction in intestinal tissue. Then we noticed that OPD could inhibit cisplatin-induced intestinal cell pyroptosis, which was indicated by the reduction of LDH release and PI positive signal in the cells and tissues. The reason is that OPD could suppress caspase-3/gasdermin E (GSDME) signaling, which is a critical mediator of chemotherapy-induced tissue injury. We also detected the upstream factors of caspase-3/GSDME signaling and have found that cisplatin-induced Reactive oxygen species (ROS) production and DNA damages could also be inhibited by OPD. Importantly, OPD administration did not reverse cisplatin-suppressed tumor burden in animals. Our present study provides a potential application of OPD to reduce cisplatin-induced side effects, without interfering the anti-tumor capacity, indicating a way to extend the duration of cisplatin administration.