This study aims to develop a wheel profile optimization procedure to minimize flange wear considering the wear evolution. To this end, the wheel wear simulation capability is integrated into the profile optimization framework such that a total material loss can be minimized under design constraints. This allows for the wear reduction to be maintained over an extended traveling distance, while an optimized profile, minimizing the frictional energy for only the initial profile, would not ensure the optimum performance after the profile wear becomes significant. Furthermore, to enable a balanced mitigation of the profile wear and surface damage, the damage index model is introduced to the weighted objective function, considering profile wear evolution. Using flange wear tests with a scaled roller test rig, wear reduction of the optimized profile is experimentally validated. The wear simulation results agree with the test data. It is demonstrated that the flange wear and tread surface damages are reduced simultaneously over an extended traveling distance using the profile optimization procedure developed in this study.