Abstract: Objective To explore the protective effect of vitamin E (VE) against radiation injury of hippocampal neurons in mice and explore the possible mechanism. Methods Cultured HT-22 and U251 cells with or without exposure to 8 Gy irradiation were treated with VE (200 μmol/L for 24 h), ferroptosis inhibitor (ferrostatin-1, 5 μmol/L for 24 h), apoptosis inhibitor (ZVAD-FMK, 2 μmol/L), or necroptosis inhibitor (100 μmol/L). MTT assay was used to evaluate the cell viability after the treatments, and reduced glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (lipid ROS), and intracellular iron ion levels were detected for assessment of ferroptosis. The mice exposed to 16 Gy irradiation with or without vitamin E (500 U/kg) treatment for 6 weeks were assessed for behavioral changes and cognitive functions using Morris water maze test. Results Treatment with VE significantly promoted the cell survival following irradiation in HT-22 cells (P<0.05) but not in U251 cells (P>0.05). Ferrostatin-1, but not ZVAD or the necroptosis inhibitor, promoted the survival of HT-22 cells following the irradiation. Exposure to irradiation significantly increased ferroptosis-related oxidative stress level in HT-22 cells, manifested by decreased GSH level and increased MDA, lipid ROS and intracellular iron ion levels (P<0.05); treatment with VE and ferrostatin-1 both obviously reversed radiation-induced ferroptosis-related oxidative stress in the cells (P<0.05). In Morris water maze test, the mice with radiation exposure showed obviously increased exploration time and distance (P<0.05), which were significantly decreased after treatment with VE (P<0.05). Conclusion Vitamin E reduces radiation injury by inhibiting ferroptosis in the hippocampal neurons in mice.