This study presents an optimization flow for structural parameters of orthotropic steel bridge decks (OSDs) based on the fatigue performance and the structural weight. The effects of structural parameters, namely, the thicknesses of the deck plate, the U-rib, the diaphragm, and the longitudinal diaphragm, on equivalent fatigue stress ranges were investigated using surrogate modelling based on the response surface methodology (RSM). Finally, the Pareto optimum front was obtained via the nondominated sorting genetic algorithm II (NSGA-II). The results show that the established surrogate response surface model can predict the local equivalent stress amplitudes well. The deck thickness is the most significant factor for the fatigue performance of the deck to U-rib weld and the U-rib to diaphragm weld. The objectives of minimizing the equivalent stress range and the total structural weight are truly conflicting, and the optimum solutions for structural parameters can be obtained from the Pareto optimum front.