To study the influence of the lateral deformations of a simply-supported beam bridge on the safety of high-speed railway train operations under earthquake action, this study adopted a three-span simply-supported beam bridge with 32-m spans as an example. Finite element software ANSYS and multi-body dynamics software SIMPACK were used to establish a coupled train-bridge dynamic model subjected to seismic excitations. By adopting different ground motions and changing the peak ground acceleration (PGA) and the train speed, the effects of different earthquakes and train speeds on the train driving safety were analyzed. Several conclusions were obtained. First, the trends in train derailment coefficient, wheel load reduction rate, lateral horizontal wheelset forces, vertical accelerations of the car body, lateral accelerations of car body, and other dynamic indices were similar under different ground motions, but the actual values were different. Second, the PGA had a significant impact on the train derailment coefficient, wheel load reduction rate, lateral horizontal wheelset forces, and lateral accelerations of the car body, but little effect on the vertical accelerations of the car body. Third, the train speed affected the train derailment coefficient, wheel load reduction rate, lateral horizontal wheelset forces, vertical accelerations of the car body, and lateral accelerations of the car body, and these dynamic performance indices were positively correlated with the train speed. Fourth, in case of the earthquake with a PGA of 0.3g, a high-speed train would have to travel slower than at 280 km/h to ensure the safety and comfort of the ride.