Biological response to blast overpressure is complex and results in various and potentially non-concomitant acute and long-term deficits to exposed individuals. Clinical links between blast severity and injury outcomes remain elusive and have yet to be fully described, resulting in a critical inability to develop associated protection and mitigation strategies. Further, experimental models frequently fail to reproduce observed physiological phenomena and/or introduce artifacts that confound analysis and reproducibility. New models are required that employ consistent mechanical inputs, scale with biological analogs and known clinical data, and permit high-throughput examination of biological responses for a range of environmental and battlefield- relevant exposures. Here we describe a novel, biofidelic headform capable of integrating complex biological samples for blast exposure studies. We additionally demonstrate its utility in detecting acute transcriptional responses in the model organism Caenorhabditis elegans after exposure to blast overpressure. This approach enables correlation between mechanical exposure and biological outcome, permitting both the enhancement of existing surrogate and computational models and the high-throughput biofidelic testing of current and future protection systems.