A mechanized and integrated computational scheme is introduced to determine the human brain responses in an environment where the human head is exposed to explosions from trinitrotoluene (TNT), or other high-yield explosives, in military applications. The procedure is based on a three-dimensional (3-D) non-linear finite element method (FEM) that implements a simultaneous conduction of explosive detonation, shock wave propagation, blast–head interactions, and the confronting human head. The processes of blast propagation in the air and blast interaction with the head are modeled by an Arbitrary Lagrangian–Eulerian (ALE) multi-material FEM formulation, together with a penalty-based fluid/structure interaction (FSI) algorithm. Such a model has already been successfully validated against experimental data regarding air-free blast and plate–blast interactions. The human head model is a 3-D geometrically realistic configuration that has been previously validated against the brain intracranial pressure (ICP), as well as shear and principal strains under different impact loadings of cadaveric experimental tests of Hardy et al. [Hardy W. N., C. Foster, M. Mason, S. Chirag, J. Bishop, M. Bey, W. Anderst, and S. Tashman. A study of the response of the human cadaver head to impact. Proc. 51 st Stapp. Car Crash J. 17–80, 2007]. Different scenarios have been assumed to capture an appropriate picture of the brain response at a constant stand-off distance of nearly 80 cm from the core of the explosion, but exposed to different amounts of a highly explosive (HE) material such as TNT. The overpressures at the vicinity of the head are in the range of about 2.4–8.7 atmosphere (atm), considering the reflected pressure from the head. The methodology provides brain ICP, maximum shear stresses and maximum principal strain within the milli-scale time frame of this highly dynamic phenomenon. While focusing on the two mechanical parameters of pressure, and also on the maximum shear stress and maximum principal strain to predict the brain injury, the research provides an assessment of the brain responses to different amounts of overpressure. The research also demonstrates the ability to predict the ICP, as well as the stress and strain within the brain, due to such an event. The research cannot identify, however, the specific levels of ICP, stress and strain that necessarily lead to traumatic brain injury (TBI) because there is no access to experimental data regarding head–blast interactions.