Professional athletes conduct high-intensitive hypoxic training often accompanied by the increase of many inflammatory-related cytokines and immunosuppression. Cucurbitacin E (CucE), as a triterpenoid isolated from Cucurbitaceae plants, exert potential anti-cancer and anti-inflammatory. However, it is unknown whether that the CucE could be used as dietary supplement for athletes to improve inflammatory response and immunosuppression. In this study, we established the simulative hypoxic training rat and monkey models and evaluated the effects of CucE on immune- and inflammation-related factors. Obvious improvement on pro-inflammatory factors and pro-lymphocyte proliferation activities were showed in CucE treated rats compared with the control. Further supplement of CucE in professional meals for cynomolgus monkeys with 4-weeks high-intensitive hypoxic training also exert effects on altitude-induced oxidative stress, inflammation and immunologic function. Furtherly, we explored the underlying mechanism of CucE in human Jurkat T cells and results showed that CucE may exhibit immunosuppressive effect by attenuating critical cytokine expression through down-regulating the NF-κB signaling pathway. In conclusion, CucE is expected to be a potential dietary supplement for athletes to ameliorate the inflammation and immunosuppression caused by high-intensitive exercise.