To alleviate the problems of the aerodynamic shape optimization (ASO) method of bridge section based on wind tunnel test, such as manpower and material cost as well as limited search range, the ASO method of main girder based on numerical calculation and mathematical strategy was proposed. Taking the streamlined box girder of Sutong Changjiang Bridge as an example, the lower web inclination angle and beam height were selected as design variables, the computational fluid dynamics (CFD) simulation and flutter time domain method were adopted as numerical calculation methods to replace the wind tunnel test, the experimental design, hybrid ant colony genetic algorithm, and Kriging model were used as the collaborative mathematics strategy to replace the trial-and-error method, and the optimal parameter matching scheme of the flutter performance of the beam section was explored. The optimization results show that the critical flutter wind speed of the optimal section in the design domain was 8% higher than that of the original section. The lower web inclination angle had a greater influence on the flutter performance than the beam height, and there was interaction between the two variables. The numerical ASO method of main beam section could better replace the wind tunnel test for shape optimization, and the research could be used as reference for the selection of long-span bridge sections.