Due to the special characteristics of rail vehicles, wheel–rail excitation has always had a huge impact on the stable operation of the vehicle system and the dynamic performance of each component structure. This paper takes high-speed train gearbox as the research object and establishes a rigid-flexible coupling dynamics model and analyses the dynamic response and fatigue damage of the gearbox under the excitation of wheel flat and wheel polygon. Combined with the analysis of test data from the gear transmission testrig and actual line operation of high-speed trains, it shows that high-speed train gearboxes are different from those applied in other fields, where the gear meshing excitation is no longer its main excitation source, but the wheel–rail excitation instead. The comparison analysis between the wheel flat and wheel polygon conditions indicates that the response of the gearbox to the wheel flat excitation is similar to the operational modal test and is capable of causing multi-order modal vibration of the gearbox. The effect of the wheel polygon on the gearbox is similar to that of single-frequency excitation, which lead to certain order modal resonance in the gearbox under frequency coupling situations. The impact of both conditions on gear box fatigue damage increases with the vehicle operating speed.