Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE sufficient (wildtype) or deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardio-pulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia and decreased compliance, all of which were attenuated in RAGE −/− mice. Neutralizing systemic HMGB1, induced by TBI, reversed hypoxia and improved lung compliance. Compared to wildtype donors, lungs from RAGE−/− TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung pre-transplantation and predicted impaired oxygenation post-transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway prior to transplant may improve recipient outcomes following lung transplantation.