OBJECTIVE To investigate the neuroprotective effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on radiation-induced brain injury (RIBI). METHODS Thirty female C57BL/6 mice were randomly divided into three groups: control (CON), whole brain irradiation (WBI), and the cell therapy (MSC) group. Mice in the WBI and MSC groups received a single, whole brain irradiation treatment with 15 Gy of 60Co. Learning and memory were evaluated in the mice using the step-down avoidance test. The neuronal changes in the hippocampal cornu ammonis (CA) 1 region were observed using hematoxylin eosin (H&E) staining. The changes in astrocytes were visualized with glial fibrillary acidic protein immunohistochemistry, and the expression of TNF-α, IL-6, and IL-10 was detected by quantitative polymerase chain reaction (qPCR) along with Enzyme linked immunosorbent assay (ELISA). RESULTS Compared with mice in the WBI group, learning and memory in the MSC mice were significantly increased (P<0.05), neuronal degeneration and necrosis were significantly decreased (P<0.05), and the number of astrocytes was significantly increased (P<0.05). The levels of the in˙ammatory cytokines, TNF-α and IL-6, were significantly decreased (P<0.05), however, the inhibitory factor IL-10 was significantly increased (P<0.05). CONCLUSIONS UC-MSCs play a neuroprotective role by inhibiting brain cell injury and neuroinflammation.