The probability of a train running over a bridge when an earthquake occurs is increasing with the total mileage of China’s high-speed railway network expanding. To study this issue, a three-dimensional train-track-bridge dynamic interaction system subjected to seismic excitations is established based on commercial mathematical software. Besides, a set of motion equations of the system are derived according to the multibody dynamics, the finite element method theory and the bridge seismic theory. Moreover, in order to study the dynamic response of high-speed railway bridges under earthquake, a series of experiments are conducted on a scaled high-speed railway simple supported bridge model with a ballastless track slab excited by shaking table tests. Meanwhile, the strain of rails, track slabs, base plates and girder in various working conditions are measured by quasi-distributed optical fiber sensing stuck in bridge members. At last, the dynamic response of each structure member is demonstrated in the time and frequency domains. Furthermore, the seismic isolation performance of bridge members, such as fasteners, cement asphalt (CA) mortar layer and so on, is explained in details.