Despite the rapid development of vehicle intelligent technology, the aerodynamic noise problem of internal combustion engine vehicles and pure electric vehicles at high speed has always been a growing problem. In this study, the effects of the car body fender shape on the aerodynamic noises of the rearview mirror and wheel region were investigated, and a noise reduction method was also proposed by optimizing the fender shape. To realize the parametric modeling of the fender, five positional variables were selected to define the fender configuration; the free-form deformation (FFD) method was used to establish the response fender model according the DOE schemes, and computational fluid dynamics (CFD) simulations are used to obtain the noise results. Then, with the help of the radial basis function (RBF) model and the adaptive simulated annealing (ASA) algorithm, the aerodynamic shape of the fender was optimized to reduce aerodynamic noise. Comparative analysis was then employed to assess flow field characteristics of the optimized model against the original model and elucidate the fender configuration’s contribution to aerodynamic noise reduction and its realization mechanism.