A mouse model of repeated blast exposure was developed using a compressed air-driven shock tube, to study the increase in severity of traumatic brain injury (bTBI) after multiple blast exposures. Isoflurane anesthetized C57BL/6J mice were exposed to 13.9, 20.6, and 25 psi single blast overpressure (BOP1) and allowed to recover for 5 days. BOP1 at 20.6 psi showed a mortality rate of 2% and this pressure was used for three repeated blast exposures (BOP3) with 1 and 30 min intervals. Overall mortality rate in BOP3 was increased to 20%. After blast exposure, righting reflex time and body-weight loss were significantly higher in BOP3 animals compared to BOP1 animals. At 4 h, brain edema was significantly increased in BOP3 animals compared to sham controls. Reactive oxygen species in the cortex were increased significantly in BOP1 and BOP3 animals. Neuropathological analysis of the cerebellum and cerebral cortex showed dense silver precipitates in BOP3 animals, indicating the presence of diffuse axonal injury. Fluoro-Jade B staining showed increased intensity in the cortex of BOP3 animals indicating neurodegeneration. Rota Rod behavioral test showed a significant decrease in performance at 10 rpm following BOP1 or BOP3 at 2 h post-blast, which gradually recovered during the 5 days. At 20 rpm, the latency to fall was significantly decreased in both BOP1 and BOP3 animals and it did not recover in the majority of the animals through 5 days of testing. These data suggest that repeated blast exposures lead to increased impairment severity in multiple neurological parameters of TBI in mice.