To study the critical speeds of safety operation for high-speed trains under different crosswind (with a wind direction angle of 90°), the crosswind speeds were set to 5, 10, 15, 20, 25, 30, and 35 m/s, respectively, and multiple operating conditions with train speeds of 200, 250, 300, 350, and 400 km/h were numerically simulated using MATLAB to obtain aerodynamic load values under different operating conditions, meanwhile, the irregularity spectrum of China's high-speed railway ballastless track was selected for numerical simulation. A multi-body system dynamics model for high-speed trains based on SIMPACK was established, using time-domain irregularity samples transformed from track irregularity spectra as track irregularity excitations, and the obtained aerodynamic load values were used as external excitation inputs to simulate and analyze the vehicle models of high-speed trains under different conditions, therefore, the safety operation indicators under different wind speeds and train speeds were obtained. The maximum speed limit for safety operation of high-speed trains under different wind speeds was given, and the safety operating range of high-speed trains was obtained by numerical fitting methods. The results showed that the lateral force of wheel shaft first exceeds the limit value with the increase of wind speed or vehicle speed, and special attention should be paid to the impact of the indicator on the safety operation of high-speed trains. When the crosswind wind speeds or train speeds is too high, it is necessary to set certain speed limits or adopt control measures to ensure the safety operation of train.