Nowadays, one of the most sensible issues in the railway industry is the damage on vehicles caused by the track conditions and the infrastructure deterioration due to the trains’ passage. Therefore, it is essential to acquire a better understanding on how the operation conditions influence the wear evolution of the railway wheels and the consequences of their changing profiles on vehicle–track interaction forces. In this work, a computational tool is used to simulate the dynamic performance of integrated railway systems and to predict the wear evolution of wheel profiles. The tool is applied to realistic operational scenarios with the purpose to evaluate the influence of the track conditions, defined by the track geometry and by its irregularities, on the wear progression of railway wheels. The loads imposed to the railway infrastructure by a trainset running at different velocities, on a track with and without irregularities, and equipped with wheelsets having new and worn profiles is also studied. The studies performed here show that the levels of track irregularities considered have a negligible influence on the wear progression. Furthermore, the loads imposed to the track during trainset operation are not affected by the wear state of the wheels. On the other hand, the track imperfections can affect significantly the vehicle–track interaction forces.