Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide, affecting both civilians and military personnel. Animal models have been developed to replicate various aspects of human TBI, aiding in the understanding of pathophysiology and the development of treatments. However, promising neuroprotective drugs identified in animal models have often failed in clinical trials, highlighting the need to revisit the current status of animal models and therapeutic strategies. TBI is a complex disease process involving primary and secondary injuries. Primary injury results from immediate mechanical disruption, while secondary injury involves metabolic, cellular, and molecular cascades leading to cell death and tissue damage. Animal models, particularly those using rodents, are essential for studying these mechanisms and developing new treatments. Common models include fluid percussion injury (FPI), cortical impact injury (CCI), weight drop–impact acceleration injury, and blast injury. Despite their utility, animal models have limitations, including physiological differences between species, injury severity measurement challenges, and the need for rigorous testing of therapeutic approaches. Future research should focus on improving the translation from animal models to clinical practice by addressing these limitations and incorporating more clinically relevant factors such as comorbidities, age, and sex differences. In conclusion, overcoming the lack of effective treatments for TBI requires a multifaceted approach, including innovative clinical trial designs, the development of new models, and the optimization of therapeutic dosing and timing. Additionally, improving brain drug delivery systems and monitoring target drug levels are crucial for effective treatment.Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide, affecting both civilians and military personnel. Animal models have been developed to replicate various aspects of human TBI, aiding in the understanding of pathophysiology and the development of treatments. However, promising neuroprotective drugs identified in animal models have often failed in clinical trials, highlighting the need to revisit the current status of animal models and therapeutic strategies. TBI is a complex disease process involving primary and secondary injuries. Primary injury results from immediate mechanical disruption, while secondary injury involves metabolic, cellular, and molecular cascades leading to cell death and tissue damage. Animal models, particularly those using rodents, are essential for studying these mechanisms and developing new treatments. Common models include fluid percussion injury (FPI), cortical impact injury (CCI), weight drop–impact acceleration injury, and blast injury. Despite their utility, animal models have limitations, including physiological differences between species, injury severity measurement challenges, and the need for rigorous testing of therapeutic approaches. Future research should focus on improving the translation from animal models to clinical practice by addressing these limitations and incorporating more clinically relevant factors such as comorbidities, age, and sex differences. In conclusion, overcoming the lack of effective treatments for TBI requires a multifaceted approach, including innovative clinical trial designs, the development of new models, and the optimization of therapeutic dosing and timing. Additionally, improving brain drug delivery systems and monitoring target drug levels are crucial for effective treatment.