The gearbox shell is a key component of class A of high-speed trains. In engineering applications, the fatigue life prediction of the gearbox shell is a critical issue to be addressed. It is not feasible to obtain fatigue life results for the gearbox shell experimentally because of its long design life, lack of actual failure data, complex structure, high test cost, and material dispersion. Therefore, the cross-scale method was introduced to accurately predict the fatigue life of the gearbox shell. In this study, the entire gearbox shell is divided into two scales of “material structure.” Firstly, the S-N curve is plotted within the material layer, based on the data from the rotating bending fatigue test. Secondly, the finite element model of the gearbox shell is established within the structural layer via the simulation platform. The characteristics and random vibration of the established model are analyzed and presented. Additionally, the first ten-order frequency of modal analysis and power spectral density responses of the gearbox are obtained. The fatigue life of the gearbox shell and the safe running distance of the train are calculated by using the three-interval method and the linear cumulative damage rule, respectively, by combining the fatigue analysis from the material layer with the simulation analysis from the structure layer. Finally, to illustrate the application of the proposed method, a group of small-scale test examples is provided. The proposed method can be used in fatigue life prediction more effectively than the single finite element simulation method.