【Abstract】Objective To establish a stable mouse model of mild to moderate closed head injury and evaluate its effectiveness. Methods A total of 170 SPF-grade ICR mice were divided into the sham group(n=34) and the TBI group (n=136). The TBI group was subjected to brain injury by impact under conditions A-D, with 34 mice in each subgroup. After modeling, the score of mNss, fatigue rotating test, and Morris water maze test were used to assess the balance and learning ability of the mice; brain water content experiment, Evans blue experiment, HE staining, GFAP immunohistochemistry, and TUNEL immunofluorescence were used to analyze pathological changes in brain tissue. Results Compared with Sham group, mNss score and water maze escape latency were increased to varying degrees in TBI group, while stick stay time was decreased significantly, indicating that severe neurological dysfunction occurred in TBI group. Brain water content and evans blue content in brain tissue of TBI group mice were significantly higher than those in sham group, suggesting that they suffered from blood-brain barrier damage and brain edema. Histopathological examination showed that the neurons in the brain tissue of the TBI group showed obvious degeneration and contraction, the astrocyte proliferation and the proportion of apoptotic cells increased significantly, and the damage degree increased with the increase of the weight of the blow. Comprehensive analysis revealed that a weight of 60 g or 80 g with a height of injury at 20 cm could simulate mild closed head injury in mice; while a weight of 100 g or 120 g could simulate moderate closed head injury in mice. Conclusion A stable mouse model of mild to moderate closed head injury was established based on the principle of free fall, which laid the foundation for studying the mechanism and treatment strategies for mmTBI.