Wheel polygonal wear can immensely worsen wheel/rail interactions and vibration performances of the train and track, and ultimately, lead to the shortening of service life of railway components. At present, wheel/rail medium- or high-frequency frictional interactions are perceived as an essential reason of the high-order polygonal wear of railway wheels, which are potentially resulted by the flexible deformations of the train/track system or other external excitations. In this work, the effect of wheel/rail flexibility on polygonal wear evolution of heavy-haul locomotive wheels is explored with aid of the long-term wheel polygonal wear evolution simulations, in which different flexible modeling of the heavy-haul wheel/rail coupled system is implemented. Further, the mitigation measures for the polygonal wear of heavy-haul locomotive wheels are discussed. The results point out that the evolution of polygonal wear of heavy-haul locomotive wheels can be veritably simulated with consideration of the flexible effect of both wheelset and rails. Execution of mixed-line operation of heavy-haul trains and application of multi-cut wheel re-profiling can effectively reduce the development of wheel polygonal wear. This research can provide a deep-going understanding of polygonal wear evolution mechanism of heavy-haul locomotive wheels and its mitigation measures.