Traumatic brain injury (TBI) is one of the major causes of death and aftereffects in young individuals worldwide; however, efficient therapies for TBI are lacking at present. High mobility group box-1 (HMGB-1), which is recognized as a representative of danger-associated molecular patterns (DAMPs), plays an important role in triggering inflammatory responses in many types of diseases. We presented the involvement of HMGB-1 in TBI and evaluated the ability of intravenously administered neutralizing anti-HMGB-1 monoclonal antibody (mAb) to attenuate brain injury. Anti-HMGB-1 mAb may provide a novel and effective therapy for TBI by protecting against blood brain barrier disruption and reducing the inflammatory responses induced by HMGB-1.