Lower extremity injuries, especially in the foot and ankle region, are frequent and severe in frontal automotive collisions and often lead to impairment and long-term disabilities. Such injuries are also more common among female drivers, than male, in comparable motor vehicle crashes. Since these injuries can lead to costly rehabilitation, it is important to better understand their distribution and causation among different sexes. Accordingly, the goal in this study is to utilise biofidelic human body models to simulate foot and ankle injuries when the occupant is subject to a wide range of field representative frontal impact scenarios, and to investigate the distribution of ankle injuries among females and males. We also investigated the effects of different foot placements, brake pedal vs toepan, on resulting injuries. To achieve this, we employed the Design of Experiments approach to simulate over 300 frontal impact scenarios with variations in vehicle crash parameters and relative occupant positions. We also introduced a new bone fracture criteria to reliably identify skeletal injuries. Simulated results show that females have a greater risk of ankle injury than males, and the right foot (positioned on the brake pedal) has higher risk of ankle injuries than the left foot (positioned in the toepan).