Taking Yujiang River Bridge on Nanning-Guangzhou railway line as study background, the refined numerical simulation model of whole vehicle and whole bridge system for coupled vibration analysis is set up. The dynamic analysis model of the cable-stayed bridge is established by finite element method, and the natural vibration properties of the bridge are analyzed. The German ICE Electric Multiple Unit (EMU) train refined three-dimensional space vehicle model is set up by multi-system dynamics software SIMPACK, and the multiple non-linear properties are considered. The space vibration responses are calculated by co-simulation based on multi-body system dynamics and finite element method when the ICE EMU train passes the long span cable-stayed bridge at different speeds. In order to test if the bridge has the sufficient lateral or vertical rigidity and the operation stability is fine. The calculation results show: The operation safety can be guaranteed, and comfort index is “excellent”. The bridge has sufficient rigidity, and vibration is in good condition.