Objective To investigate the protective effect of polydatin on mice with radiation induced brain injury. Methods A total of 40 mice were randomly assigned to control group, polydatin group, radiation group, or radiation+polydatin group, with 10 mice in each group. Mice of the radiation and radiation+polydatin groups received 60CO γ irradiation in 20 Gy, whereas the control group and the polydatin group received 60CO γ irradiation in 0 Gy, for a 7⁃day irradiation. During irradiation, mice of the polydatin and radiation+polydatin groups received intraperitoneal injection of 1% polydatin solution in 100 mg/kg, while mice of the control group and the radiation group received intraperitoneal injection of normal saline in equivalent volume. The Morris water maze test was adopted to evaluate learning and memory function of mice in various groups. The hematoxylin⁃eosin staining was employed to observe pathological changes of brain tissues in mice. The immunohistochemical staining method was used to detect number of microglial positive synapse, and cell body areas of microglial cells, astrocytes, as well as expressions of fibrinogen (FIB), and CD31, and number of microvessels in brain tissues of mice. Results Compared with before irradiation, mice of the radiation group obtained prolonged escape latency and reduced platform⁃crossing times after irradiation (P<0.05), and the motion trajectory was random. After irradiation, compared with the control group, mice of the radiation group acquired prolonged escape latency and reduced platform⁃crossing times (P<0.05), and the motion trajectory was random; furthermore, compared with the radiation group, mice of the radiation+polydatin group presented as shortened escape latency and increased platform⁃crossing times (P<0.05), and the motion trajectory was more focused on the target quadrant. Compared with the control group, mice in the radiation group presented as disordered brain tissue structure, obvious nucleus contraction, decreased number of vessels; in addition, compared with the radiation group, mice in the radiation+polydatin group presented as significantly ameliorated brain tissues disorder. Compared with the control group, the radiation group exhibited increased cell body area of microglial cells, decreased microvessel number, increased intravascular FIB deposition, and decreased CD31 expression in brain tissues of mice (P<0.05). Compared with the radiation group, the radiation+polydatin group interpreted reduced cell body area of microglial cells, reduced synaptic number, reduced cell body area of astrocytes, increased microvessel number, decreased intravascular FIB deposition, and elevated CD31 expression (P<0.05). Conclusion Polydatin can improve cerebral vascular integrity through relieving neuroinflammatory response in mice with radiation induced brain injury, so as to relieve learning and memory dysfunction, recover cerebral nervous system function.