To examine the effect of the wheel polygonization on the fatigue of the wheelset-mounted gearbox housing of a high-speed train, a three-dimensional multibody system (MBS) railway vehicle model, which accounts for the flexibilities of gearbox housing and wheelset and the nonlinear wheel-rail contact, is established to perform the finite element and multibody dynamics analysis simultaneously. Field measurements on the wheel wear, within a total running distance of 140,000 km, were conducted to state the evolution of polygonal wear with a dominant order of 20 on the wheel. Then this uneven wear on the wheel is treated as excitations in the wheel-rail interaction, followed by numerical analysis on the dynamics stress distribution on the gearbox housing under the effect of a variable amplitude of polygonal wear on the wheel. It shows that the stress distribution on the gearbox housing is significantly affected by the deformation of the wheelset. Furtherly, the Kernel density estimation (KDE) method is employed to extrapolating the dynamic stress on the gearbox to obtain the stress with a total running distance of 140,000 km, then its fatigue damage is estimated. Comparative analysis in the fatigue damage of gearbox housing with or without the wheel polygonization states that the fatigue damage with a 20th order polygonal wear is 63% larger than that without the polygonal wear on the wheel.