Explosions cause the majority of injuries in the current conflicts, accounting for 79% of combat related injuries (Ramasamy et al. 2008). Blast overpressure from explosions can cause barotrauma to the lungs and the brain. Blast-induced mild traumatic brain injury has been labeled the ‘signature wound’ of current military conflicts in Iraq and Afghanistan (Snell and Halter 2010). In addition to elevated number of blast-induced traumatic brain injuries due to increased military conflicts overseas and the usage of improvised explosive devices, the incidence of blastinduced polytrauma has risen due to the prevalence of terrorist events around the world (Arnold et al. 2004, Rodoplu et al. 2004). Blast-induced polytrauma is a major concern as lung injury can cause immediate mortality and brain injury causes long-lasting neurocognitive impairment. There is a critical lack of understanding the pathology of blast-induced polytrauma since the needs are multifaceted and therefore few options for treatment. Thus, the research presented in this dissertation required the development of a military-relevant blast polytrauma model to examine injury pathology and subsequently study the effects of hemostatic nanoparticle therapy after blast-induced polytrauma. The pre-clinical model was characterized and static overpressure thresholds were determined for lethality risk. It was confirmed to have many of the classic hallmarks of primary blast lung injury (PBLI), as well as blast-induced neurotrauma (BINT) (Clemedson 1950). Global hemorrhaging was found in the lungs and well as reduced oxygen saturation. Markers of astrogliosis and blood-brain barrier disruption were examined in the amygdala after blast. The novel nanoparticle configuration (hemostatic dexamethasone-loaded nanoparticles (hDNP) functionalized with a peptide that binds with activated platelets) was investigated and hypothesized to increase survival, reduce cellular injury and reduce anxiety-like disorders after blast polytrauma. After investigating hDNP, it was found that the hDNP treatment benefited survival percentage after injury as well as reduced percent hemorrhage in the lungs and improved physiology. Elevated anxiety parameters found in the controls were lower as compared to the hDNP group. Glial fibrillary acidic protein (GFAP) and cleaved caspase-3 were significantly elevated in the controls compared to the hDNP group in the amygdala. SMI-71 was also significantly elevated with the hDNP and hemostatic nanoparticle (hNP) treatments, similar to sham. In addition to the nanoparticles offering immediate life-saving qualities, administration of hemostatic nanoparticles improved amygdala pathology attributed to secondary mechanisms of blast injury, including blood-brain barrier disruption. This model of polytrauma can serve as a foundation for detailed pathological studies as well as testing therapeutics for injury modalities.