This work presents a detailed investigation conducted into the relationships between wheel polygonal wear and wheel/rail noise, and the interior noise of high-speed trains through extensive experiments and numerical simulations. The field experiments include roundness measurement and characteristics analysis of the high-speed wheels in service, and analysis on the effect of re-profiling on the interior noise of the high-speed coach. The experimental analysis shows that wheel polygonal wear has a great impact on wheel/rail noise and interior noise. In the numerical simulation, the model of high-speed wheel/rail noise caused by the uneven wheel wear is developed by means of the high-speed wheel-track noise software (HWTNS). The calculation model of the interior noise of a high-speed coach is developed based on the hybrid of the finite element method and the statistic energy analysis (FE-SEA). The numerical simulation analyses the effect of the polygonal wear characteristics, such as roughness level, polygon order (or wavelength), and polygon phase, on wheel/rail noise and interior noise of a high-speed coach. The numerical results show that different polygon order with nearly the same roughness levels can cause different wheel/rail noises and interior noises. The polygon with a higher roughness level can cause a larger wheel/rail noise and a larger interior noise. The combination of different polygon phases can make a different wheel circle diameter difference due to wear, but its effect on the interior noise level is not great. This study can provide a basis for improving the criteria for high-speed wheel re-profiling of China’s high-speed trains.