Traumatic brain injury (TBI) is the leading cause for high morbidity and mortality rates in young adults, survivors may suffer from long-term physical, cognitive, and/or psychological disorders. Establishing better models of TBI would further our understanding of the pathophysiology of TBI and develop new potential treatments. A multitude of animal TBI models have been used to replicate the various aspects of human TBI. Although numerous experimental neuroprotective strategies were identified to be effective in animal models, a majority of strategies have failed in phase II or phase III clinical trials. This failure in clinical translation highlights the necessity of revisiting the current status of animal models of TBI and therapeutic strategies. In this review, we elucidate approaches for the generation of animal models and cell models of TBI and summarize their strengths and limitations with the aim of exploring clinically meaningful neuroprotective strategies.