Objective The objective of this study is to examine the effects of seatback angle, seat rotation, and impact speed on occupant kinematics and injury risk in highly automated vehicles. Methods The study utilized the Global Human Body Models Consortium midsize male (M50-OS+B) simplified occupant model in a simplified vehicle model (SVM) to simulate frontal crashes. The M50-OS+B model was gravity-settled and belted into the driver and left rear passenger seat. To investigate the effects of seatback angle, seat rotation, and impact speed on occupant kinematics and injury risk in frontal crashes, a design of experiments (DOE) was conducted. The DOE incorporated four seatback angles (13°, 23°, 45°, and 57.5° about vertical), four seat rotation angles (0°, 25°, 45°, and 90°), three impact speeds (25, 35, and 45 kph), and four frontal crash type configurations. All four seatback angles were used with 0° seat rotation, whereas 13° seatback angle was used with the remaining seat rotation configurations because of cabin fit considerations. Injury risks were estimated for the head, neck, shoulder, thorax, pelvis, and lower extremities for both occupants for each simulation (n=588). Results Statistically significant differences between all the groups within each independent variable category were observed based on the analysis of variance. HIC-based head injury risk and chest injury risk decreased and femur force for the driver and tibia force for the passenger increased with an increase in seatback angles. The head injury risk increased with seat rotation. All the injury risks increased with an increase in impact speed. The driver airbag was able to safeguard the driver from head injuries for all seat rotations except at 90° of seat rotation. Conclusion This is the first vehicle modeling study that collectively looked at the effects of seatback angle, seat rotation, and impact speed along with the interaction of occupants on the risk of injury in frontal crashes. The rear passenger experienced higher seatbelt loads than the driver. More reclined seats decreased head and chest injury risk, but increased driver femur injury risk and rear passenger tibia injury risk. Results underscore the necessity for additional anti-submarining mechanisms and driver airbag designs adapted for the anticipated occupant positions.