With multiaxial fatigue model and rigid-flexible coupling dynamic model, the effects of polygonal wave amplitude, running speed, and axle load on multiaxial fatigue damage of high-speed train axle are studied considering wheel polygonization. The results indicate that an increase in polygonal wave amplitude will lead to an increase in the maximum and range of the axle’s stress components, thereby reducing the service life of the axle. When the frequency excited by wheel polygonization is near the modal frequency of the wheelset, the dynamic stress of the axle is higher than the allowable safety stress, and the service life of the axle is much lower than the design life. The axle load will affect the service life of the axle by affecting the maximum dynamic stress. Under the condition of wheel polygonization, appropriately reducing axle load can greatly improve the service life of the axle. Therefore, to ensure operation safety, the influence of wheel polygonization should be fully considered in the design stage of the axle.