In order to evaluate the safety of the long-span suspension bridge structure located in the wind field and the running stability of the train under the dynamic loading of the train, the FLUENT software was used to conduct CFD analysis on the flow field of the main girder section of a certain long-span suspension bridge for both highway and railway to obtain the three-component force coefficients of the main girder, and the wavelet analysis method was used to simulate the fluctuating wind velocity time history around the bridge as the external excitation for the vibration response calculation of the train-bridge dynamic interaction system. At the same time, the track irregularity and the wheel-set hunting were considered, a coupled vibration analysis model of the wind-train-bridge system was established, and the calculation program was written to simulate the dynamic responses of the bridge and the vehicle, and the running safety and ride comfort of the train under different working conditions were analyzed in detail. Results show that wind velocity has a more significant impact on the dynamic response of the bridge. Moreover, the lateral displacement is more easily affected by wind load; The lateral acceleration of the vehicle increases sharply with the increase of wind velocity and train running speed, while its vertical acceleration changes less; When the average wind velocity exceeds 20 m/s, the operational safety of a high-speed train running at 300 km/h cannot be guaranteed. The research results can provide a reference for the wind and vibration resistance design of similar bridges.