Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality all over the world. The knowledge and understanding of pathophysiology of TBI are the priority as a basic to develop therapeutic opportunities and allow improvement of outcome for TBI patients. In TBI, primary damage occurs at the time of impact and the damage is preventable but not treatable. The process will continue caused following trauma due to complicating processes. Secondary brain insults have been found in many patients of severe TBI. This insult continues, which involves complex molecular and genes cascades, and is not fully understood. Chronic microglia activation and epigenetic mechanism were potential entry point in third brain damage processes. We suggest that treatment of tertiary insults might be ameliorate chronic complication of severe TBI patients.