In this study, we propose an optimization method for occupant protection systems using a machine learning technique. First, a crash simulation model was developed for a Euro NCAP MPDB frontal crash test condition. Second, a series of parametric simulations were performed using a THOR dummy model with varying occupant safety system design parameters, such as belt attachment locations, belt load limits, crash pulse, and so on. Third, metamodels were developed using neural networks to predict injury criteria for a given occupant safety system design. Fourth, the occupant safety system was optimized using metamodels, and the optimal design was verified using a subsequent crash simulation. Lastly, the effects of design variables on injury criteria were investigated using the Shapely method. The Euro NCAP score of the THOR dummy model was improved from 14.3 to 16 points. The main improvement resulted from a reduced risk of injury to the chest and leg regions. Higher D-ring and rearward anchor placements benefited the chest and leg regions, respectively, while a rear-loaded crash pulse was beneficial for both areas. The sensitivity analysis through the Shapley method quantitatively estimated the contribution of each design variable regarding improvements in injury metric values for the THOR dummy.