Traumatic brain injury sustained after blast exposure (blast-induced TBI) has recently been documented as a growing issue for military personnel. Incidence of injury to organs such as the lungs has decreased, though current epidemiology still causes a great public health burden. In addition, unprotected civilians sustain primary blast lung injury (PBLI) at alarming rates. Often, mild-to-moderate cases of PBLI are survivable with medical intervention, which creates a growing population of survivors of blast-induced polytrauma (BPT) with symptoms from blast-induced mild TBI (mTBI). Currently, there is a lack of preclinical models simulating BPT, which is crucial to identifying unique injury mechanisms of BPT and its management. To meet this need, our group characterized a rodent model of BPT and compared results to a blast-induced mTBI model. Open field (OF) performance trials were performed on rodents at 7 days after injury. Immunohistochemistry was performed to evaluate cellular outcome at day seven following BPT. Levels of reactive astrocytes (GFAP), apoptosis (cleaved caspase-3 expression), and vascular damage (SMI-71) were significantly elevated in BPT compared to blast-induced mTBI. Downstream markers of hypoxia (HIF-1α and VEGF) were higher only after BPT. This study highlights the need for unique therapeutics and prehospital management when handling BPT.