Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity in young individuals worldwide. However, the understanding of TBI at secondary phase remained obscure, and more knowledge of the pathophysiology of TBI is necessary. In this study, we examined the influence of bone fracture (BF) on TBI and investigated whether blocking high mobility group 1 (HMGB1) protein, an inflammatory mediator, could be effective to alleviate TBI. We found neurological severity was significantly increased by BF at 4days post-TBI with longer removal time of adhesive tape and higher percentage of left turn in the corner test compared to TBI treatment alone. Additionally, higher brain lesion volume and severer brain oedema in TBI+BF mice supports the negative effect of BF on TBI. HMGB1 level was significantly stimulated by BF, suggesting the important role of HMGB1 in the development of secondary TBI. Notably, ablation of HMGB1 significantly reduced this negative influence of BF on TBI. These results suggest that HMGB1 can be massively induced by the systemic immune activation triggered by BF, which in turn aggravates inflammation. Blocking HMGB1 reduced the inflammatory effect of BF and therefore helps lessen the severity of secondary TBI. In conclusion, these results provided the evidence that anti-HMGB1 may be an effective and feasible method to alleviate TBI.