Abstract: Objective To investigate the protective effect of Jiawei Shengmai powder on rat small intestine erypt epithelial cells(IEC-6) and rats with intestinal injury induced by ionizing radiation, and to explore its potential mechanism through the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pyroptosis pathway. Methods IEC-6 cells were divided into blank control group, model group, NLRP3 silencing group, and Jiawei Shengmai powder treatment groups, and 8 Gy ionizing radiation was used to induce cell damage. Additionally, rats were divided into control group, model group, and Jiawei Shengmai powder treatment group, where 10 Gy ionizing radiation was used to establish a radiation-induced enteritis model. Then, MTT assay, flow cytometry, ELISA, and Western blot were used to detect cell viability, pyroptosis level, and expression of inflammatory factors. Based on pathological observation of rat intestinal tissue, the protective effect of Jiawei Shengmai powder and its regulatory role in oxidative stress and inflammatory response were evaluated. Results Compared with the model group, the NLRP3 silencing group and Jiawei Shengmai powder treatment group significantly increased the viability of IEC-6 cells, reduced the level of pyroptosis, and decreased the expression of Caspase-1 (P<0.01). In the rat model, Jiawei Shengmai powder significantly improved radiation-induced intestinal injury, reduced oxidative stress and inflammatory response (P<0.01). Conclusions Jiawei Shengmai powder mitigates ionizing radiation-induced damage to IEC-6 cells and rat intestines by inhibiting the NLRP3 pyroptosis pathway, exhibiting anti-inflammatory, antioxidant, and pyroptosis-suppressing effects. These findings provide a potential new approach for the prevention and treatment of radiation-induced enteritis.