Traumatic brain injury (TBI) contributes to a substantial number of deaths and cases of permanent disability annually. An immune response to head injury gives a timeline to the pathological cascades with multiple cellular, metabolic and immune pathways activated from the moment of injury. In addition to the primary brain injury which refers to an unavoidable brain damage that occurs at the immediate moment of impact, secondary brain injury develops in the latter term, progressively contributing to the worsened neurological outcome. This complex phenomenon is defined by the various neurochemical cascades activated, and the systemic physiological responses which manifest in the afterwards the traumatic event. Microglial activation and macrophage accumulation after diffuse brain injury is observed within 6 to 48 hours post injury. Thus, diffuse brain injury mediated immune responses, blood-brain barrier alterations, oxidative stress and neuroinflammation seem to play an important role in the pathology.