As early as the 1950's, Gurdjian and colleagues (Gurdjian et al. 1955) observed that brain injuries could occur by direct pressure loading without any global head accelerations. This pressure-induced injury mechanism was "forgotten" for some time and is being rekindled due to the many mild traumatic brain injuries attributed to blast overpressure. The aim of the current study was to develop a finite element (FE) model to predict the biomechanical response of rat brain under a shock tube environment. The rat head model, including more than 530,000 hexahedral elements with a typical element size of 100 to 300 microns was developed based on a previous rat brain model for simulating a blunt controlled cortical impact. An FE model, which represents gas flow in a 0.305-m diameter shock tube, was formulated to provide input (incident) blast overpressures to the rat model. It used an Eulerian approach and the predicted pressures were verified with experimental data. These two models were integrated and an arbitrary Lagrangian-Eulerian (ALE) fluid-structure coupling algorithm was then utilized to simulate the interaction of the shock wave with the rat head. The FE model-predicted pressure-time histories at the cortex and in the lateral ventricle were in reasonable agreement with those obtained experimentally. Further examination of the FE model predictions revealed that pressure amplification, caused by shock wave reflection at the interface of the materials with distinct wave impedances, was found in the skull. The overpressures in the anterior and posterior regions were 50% higher than those at the vertex and central regions, indicating a higher possibility of injuries in the coup and contrecoup sites. At an incident pressure of 85 kPa, the shear stress and principal strain in the brain remained at a low level, implying that they are not the main mechanism causing injury in the current scenario.