The dynamic interactions of a high-speed train, the track, and a simply-supported girder bridge are studied by theoretical analysis in this paper. A dynamic interaction model of the train-track-bridge system is established in ANSYS. Uneven pier settlement caused by ground subsidence and measured track irregularities are taken as the system excitation. The dynamic responses of the high-speed train are used as the safety and stability evaluation indexes when it passes over the bridge. A case study considering an eight-car high-speed train running on a four-span simply supported bridge in a ground subsidence area is analyzed. Relationships among different settlement periods, different train operation modes, and running dynamic performance under various speeds are obtained. The results indicate that speed is the dominant factor affecting the safety and stability of the high-speed train where local ground subsidence is present. In addition, when the speed of the train is high and ground subsidence is greater, the degree of settlement and the operation of the high-speed train are also important factors that affect the safety and stability.