Traumatic brain injury (TBI) is a leading cause of mortality and morbidity globally, with long-term cognitive, sensorimotor, and personality impairments in survivors. Over the past three decades, animal models have been developed to replicate TBI pathophysiology and explore treatments. However, promising neuroprotective drugs identified in animal studies have failed in clinical trials, highlighting the need to revisit animal models and therapeutic strategies. TBI results from mechanical forces, leading to primary and secondary injury mechanisms. Primary injury includes contusions, hemorrhage, and axonal shearing, while secondary injury involves metabolic, cellular, and molecular cascades leading to cell death and tissue damage. Secondary injury mechanisms include glutamate excitotoxicity, calcium dysregulation, inflammation, and diffuse axonal injury. Cell death occurs within minutes and extends over days to months. Animal models of TBI are designed to produce homogeneous injuries, but may not fully replicate human TBI complexity. This review discusses various TBI animal models, including fluid percussion injury (FPI), controlled cortical impact (CCI), penetrating ballistic injury (PBBI), weight drop, and blast injury models. Each model has distinct features and is used to study different aspects of TBI. FPI models replicate intracranial hemorrhage and brain swelling but not skull fractures. CCI models mimic cortical tissue loss and axonal injury. PBBI models simulate high-energy projectile injuries. Weight drop models produce focal and diffuse injuries. Blast injury models replicate blast wave effects. These models are used to study TBI pathophysiology, neurobehavioral deficits, and therapeutic interventions. However, challenges remain in translating findings to clinical practice due to differences in injury severity, physiological responses, and outcome measures between species. Current animal models may not fully capture human TBI complexity, and further research is needed to improve models and identify effective treatments. The review emphasizes the importance of rigorous preclinical studies, including dose-response analysis, long-term studies, and consideration of comorbidities. It also highlights the need for better biomarkers and improved models to facilitate translation of findings to clinical practice. The ultimate goal is to develop effective therapies for TBI by combining innovations in clinical trial design, model development, and biomarker identification.Traumatic brain injury (TBI) is a leading cause of mortality and morbidity globally, with long-term cognitive, sensorimotor, and personality impairments in survivors. Over the past three decades, animal models have been developed to replicate TBI pathophysiology and explore treatments. However, promising neuroprotective drugs identified in animal studies have failed in clinical trials, highlighting the need to revisit animal models and therapeutic strategies. TBI results from mechanical forces, leading to primary and secondary injury mechanisms. Primary injury includes contusions, hemorrhage, and axonal shearing, while secondary injury involves metabolic, cellular, and molecular cascades leading to cell death and tissue damage. Secondary injury mechanisms include glutamate excitotoxicity, calcium dysregulation, inflammation, and diffuse axonal injury. Cell death occurs within minutes and extends over days to months. Animal models of TBI are designed to produce homogeneous injuries, but may not fully replicate human TBI complexity. This review discusses various TBI animal models, including fluid percussion injury (FPI), controlled cortical impact (CCI), penetrating ballistic injury (PBBI), weight drop, and blast injury models. Each model has distinct features and is used to study different aspects of TBI. FPI models replicate intracranial hemorrhage and brain swelling but not skull fractures. CCI models mimic cortical tissue loss and axonal injury. PBBI models simulate high-energy projectile injuries. Weight drop models produce focal and diffuse injuries. Blast injury models replicate blast wave effects. These models are used to study TBI pathophysiology, neurobehavioral deficits, and therapeutic interventions. However, challenges remain in translating findings to clinical practice due to differences in injury severity, physiological responses, and outcome measures between species. Current animal models may not fully capture human TBI complexity, and further research is needed to improve models and identify effective treatments. The review emphasizes the importance of rigorous preclinical studies, including dose-response analysis, long-term studies, and consideration of comorbidities. It also highlights the need for better biomarkers and improved models to facilitate translation of findings to clinical practice. The ultimate goal is to develop effective therapies for TBI by combining innovations in clinical trial design, model development, and biomarker identification.