Custom-molded foot orthoses are frequently prescribed in routine clinical practice to prevent or treat plantar ulcers in diabetes by reducing the peak plantar pressure. However, the design and fabrication of foot orthosis vary among clinical practitioners and manufacturers. Moreover, little information about the parametric effect of different combinations of design factors is available. As an alternative to the experimental approach, therefore, computational models of the foot and footwear can provide efficient evaluations of different combinations of structural and material design factors on plantar pressure distribution. In this study, a combined finite element and Taguchi method was used to identify the sensitivity of five design factors (arch type, insole and midsole thickness, insole and midsole stiffness) of foot orthosis on peak plantar pressure relief. From the FE predictions, the custom-molded shape was found to be the most important design factor in reducing peak plantar pressure. Besides the use of an arch-conforming foot orthosis, the insole stiffness was found to be the second most important factor for peak pressure reduction. Other design factors, such as insole thickness, midsole stiffness and midsole thickness, contributed to less important roles in peak pressure reduction in the given order. The statistics-based FE method was found to be an effective approach in evaluating and optimizing the design of foot orthosis.