Radiation proctitis (RP) refers to rectal injury caused by radiation treatment of pelvic and retroperitoneal malignancies, which seriously affects the treatment prognosis and life quality of cancer patients. However, effective medicine for treating RP has not found yet. Ginsenoside Rg3 (GRg3) is a tetracyclic triterpene saponin monomer, which is the main bioactive component of ginseng extract. In this study, we found that GRg3 significantly improved the general condition and histopathological damage on RP rats. In addition, it has been found out that GRg3 decreased the levels of pro-inflammatory factors (TNF-α) and increased the levels of anti-inflammatory factors (IL-4, IL-10). Meanwhile, RT-qPCR and Western blot assays showed that GRg3 significantly inhibited the activation of NF-κB and Caspase-8 signaling pathways. The results suggest that GRg3 may reduce the inflammatory response by inhibiting the NF-κB signaling pathway and improving the balance of inflammation-related factors. GRg3 may also inhibit intestinal cell apoptosis by suppressing the TNF-α/Caspase-8 signaling cascade, thereby reducing radiological rectal injury. Therefore, ginsenoside Rg3 may be a promising therapeutic agent for RP.