Most fatal human skull injuries occur under impact loading conditions, such as car collisions, where the strain rates fall in the range of intermediate (1/s−10²/s) and high (10²/s−10³/s) rates. Therefore, knowledge of the mechanical behaviors of human cranial bone at higher strain rates, i.e., intermediate and high strain rates, may provide insight into the prevention of skull injuries and help the design of efficient head protection systems. In the present study, the compressive mechanical behaviors of human frontal skull bone along and perpendicular to its through-the-thickness direction were experimentally characterized at quasi-static (0.01/s), intermediate (30/s) and high (625/s) strain rates in this study. A total number of 75 specimens prepared from three male donors with ages of 70–74 were separated into three groups:​ quasi-static (N = 23), intermediate (N = 23), and high (N = 29) strain rates. Experiments at quasi-static and intermediate strain rates were performed using a hydraulically driven materials testing system (MTS), while a Kolsky compression bar was used to load the skull bone specimen at high strain rates. X-ray computed tomography was performed to obtain the structural parameters and visualize the microstructures of the skull bone. The in-situ failure processes of the specimens under high-rate loading were documented by a high-speed camera. The human skull exhibited a loading-direction dependent mechanical behavior, as higher ultimate strength and elastic modulus were found in the direction perpendicular to the thickness when compared with those along the thickness direction, exhibiting an increasing ratio as high as 2 and 3 for strength and modulus, respectively. High-speed images revealed that the specimens loaded along the thickness direction generally failed due to the crushing in diploë (the trabecular bone tissue) whereas separation of the entire architecture was observed as the main failure mode when compressed in the perpendicular direction. The effect of loading rate was also evident:​ the skull specimens were increasingly brittle as strain rate increased from quasi-static to high rate for both the loading directions. The elastic modulus increased by a factor of 4 in radial direction and it increased by a factor of 2.5 in the tangential direction across the quasi-static, intermediate and high strain rates. Significant differences were also found in ultimate strength and work to failure as loading rate increased from quasi-static to high rates. The results also suggested that the strength in the radial direction was mainly depended on the diploë porosity while the diploë layer ratio played the predominant role in tangential direction.