Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI. Despite advances in the links between thrombosis and inflammation, there is a lack of treatment options aimed at both processes and this could be crucial to treating vascular injury, local and systemic inflammation, and secondary ischemic events following TBI. With emerging evidence of newly-identified roles for platelets, leukocytes, the coagulation system and extracellular vesicles in processes of inflammation and thrombosis, there is a growing need to characterize these mechanisms within the context of TBI and whether these changes persist into the chronic phase of injury. Importantly, this review defines areas in need of further research to advance the field and presents a roadmap to identify new diagnostic and treatment options for TBI.Published by Elsevier Ltd.