Modal tests were carried out to verify the accuracy of the aluminum alloy wheel model and then radial fatigue analysis was performed on the aluminum alloy wheel. The results indicate that the stress concentration area and the low life area are distributed at both ends of the weight reduction hole. On this basis, the response surface optimization method was utilized to optimize the hub structure. The error between the finite element simulation results of the optimized model and the predicted results of the response surface is within the acceptable range, which verifies the feasibility of the response surface optimization results. The optimization results reveal that the maximum stress of the hub is reduced by about 29.5 MPa, and the radial fatigue life is increased by about 3 times.