In this study, on the basis of simulation of the electric field, the design optimization methods for 120 and 250 kA magnesium electrolysis cells were developed. A 3D numerical model was built to simulate the electric field at the steady state to obtain the minimum resistance voltage which has a significant effect on the energy consumption in the magnesium electrolysis process. The major optimization was focused on adjustment of structural parameters, such as the relative positions of the anode and cathode, electrolyte height in the cell, and so on. An orthogonal design approach was used to optimize the structural parameters in a 120 kA cell, and the optimization criterion was applied to magnify the design of a 250 kA cell. The resistance voltage in the optimized 250 kA cell was computed, and the minimum resistance voltage was 1631.3 mV among the provided solutions. Hence, the developed model and simulation results would be useful for the design optimization of a magnesium electrolysis cell.