The purpose of this study was to investigate whether hemostatic dexamethasone-loaded nanoparticles (hDNP) could reduce cellular injury and improve functional outcomes in a model of blast trauma. Blood loss is the primary cause of death at acute time points post injury in both civilian and battlefield traumas. Currently, there is a shortage in treatments for internal bleeding, especially for rapid administration in open field combat. An established polytrauma model that simulates severe injury, including primary blast lung injury and blast-induced neurotrauma (BINT), was used to evaluate hDNP. Poly(lactic-co-glycolic acid)-based nanoparticles with poly(ethylene glycol) arms were functionalized with a arginine-glycineaspartic acid (RGD) peptide to target and adhere to activated platelets. Rats were exposed to a single “free field” blast wave at a peak overpressure of 28 psi for 2.5 ms duration using the Advanced Blast Simulator (ABS), operating above 50% lethality risk, in a side-thorax orientation (Hubbard, 2014). After injury, animals were immediately injected intravenously with hDNP, control dexamethasone-loaded nanoparticles (cDNP), or lactated ringers (LR). Sham animals were not injected or exposed to the blast wave. At one week post-blast, behavioral assays were performed preceding brain extraction for immunofluorescent staining using IBA-1 (activated microglia) and GFAP (activated astrocytes). Elevated anxiety parameters were found in the control and LR groups compared to the hDNP group. GFAP was significantly elevated in the control group compared to the hDNP and sham groups in the amygdala. Immediate intervention to assuage hemorrhage, one source for injury pathology, is crucial to mitigate debilitating injury mechanisms that lead to cognitive and emotional deficits (Shetty, 2014). It is possible that through prevention of neuroinflammatory cascades, hDNP were able to mitigate cellular injury and improve cognitive outcomes.