Traumatic brain injury (TBI) is the signature injury of modern military conflicts due to the prevalence of improvised explosive devices (IEDs). However, the pathobiology of blast-induced traumatic brain injury (bTBI) and its effects on the blood-brain barrier (BBB) – a structure essential for maintaining brain homeostasis – remain poorly understood. This work utilized a helium-driven shock tube to generate militarily relevant overpressure/duration histories to injure an in vitro BBB model, which exhibited integrity disruption following exposure to 571 ± 15 kPa peak incident overpressure with 1.06 ± .007 ms duration and 186 ± 1.5 kPa∙ms impulse in-air. Significant changes to barrier integrity were quantified by trans-endothelial electrical resistance (TEER), hydraulic conductivity and zona occludens-1 (ZO-1) immunofluorescence. The acute postinjury TEER dose-response suggested that a tentative threshold for blast-induced barrier opening exists between 469 kPa and 571 kPa peak overpressure. Significantly increased hydraulic conductivity indicated compromised tight junctions, confirmed by altered ZO-1 morphology and significantly reduced immunofluorescence. TEER in blast-exposed cultures remained significantly depressed compared to agematched controls up to 2 days after injury, and recovered to control levels at day 3. Elucidating BBB disruption caused by primary blast will guide the development of strategies to mitigate BBB neuropathologies associated with bTBI.