Background: Bone marrow mesenchymal stem cells (BMSCs) have demonstrated potential in the treatment of radiation-induced brain injury (RIBI); however, the presence of the blood-brain barrier (BBB) limits their therapeutic efficacy. Additionally, the precise mechanisms behind the use of BMSCs in treating RIBI are still not well understood. This study aimed to investigate the therapeutic efficacy of mannitol and BMSCs on neuronal autophagy and their efficacy in treating RIBI. Methods: In the study, RIBI models were first established in male Sprague-Dawley (SD) rats. Evans blue staining was performed to examine how mannitol influences BBB permeability in RIBI. We isolated BMSCs from SD rats using the whole bone marrow adherent method and assessed their adipogenic and osteogenic differentiation potential through Oil Red O and Alizarin Red S staining; flow cytometry analysis assessed cell surface markers. Prussian blue staining was employed to verify the migration of iron-labeled BMSCs into brain tissue. The rats were then divided into specific treatment groups, and model establishment followed according to experimental conditions. The body weight of the rats was measured weekly throughout the study. Cognitive function was assessed using the Morris water maze test. H&E and Nissl staining were applied to evaluate hippocampal neuronal survival. We quantified key proteins in the PI3K/AKT/mTOR signaling pathway by Western blotting, and quantified autophagy-related proteins LC3B and beclin-1 using both Western blotting and immunofluorescence. Results: Mannitol treatment significantly increased BBB permeability and promoted BMSCs migration. The combination of BMSCs and mannitol improved cognitive and memory functions, leading to better body weight recovery compared to the BMSCs group. H&E and Nissl staining also revealed a significant increase in neuronal survival within the combined treatment group. Furthermore, we observed through Western blot and immunofluorescence analyses that combination of BMSCs and mannitol enhanced the activation of PI3K, AKT, and mTOR through phosphorylation, while it reduced the expression levels of LC3B and beclin-1. Conclusion: The combination of BMSCs and mannitol treatment significantly improved cognitive function and hippocampal neuronal survival in RIBI rats. This effect was achieved by increasing BBB permeability, facilitating BMSCs migration to the injured region, and regulating excessive autophagy through the PI3K/AKT/mTOR pathway. This combined treatment demonstrated a neuroprotective effect superior to that of BMSCs treatment alone.