Traumatic brain injury (TBI) is a devastating disease frequently followed by significant behavioral disabilities and long-term medical complications that include a wide range of behavioral and emotional problems. TBI is characterized by a combination of immediate mechanical dysfunction of brain tissue and secondary damage developed over a longer period of time following the injury. The early inflammatory response after tissue injury can be triggered by several factors such as extravasated blood products and reactive oxygen species (ROS). It is important to note that energy generation and mitochondrial function are closely related to and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. In this context, the present review covers the preclinical and clinical literature investigating the role of inflammation and free radicals in secondary damage generated by several models of TBI. Furthermore, the present review aims to discuss the role of creatine, a guanidine compound popularly used as a performance-enhancing supplement for high-intensity athletic performance, in secondary damage induced by TBI. In this narrative review, we also discuss the beneficial effect of exercise performed in animal models of TBI and how the results from animal studies can be applied to clinical settings.