Abstract: Scour and earthquakes are two critical hazards that should be considered in the design of highway bridges crossing rivers in China. Scour erodes the soil around piles and changes the boundary condition of the bridge site, which thus affects the bridge’s seismic input. Their combined effects significantly complicate the dynamic behavior and seismic damage mechanisms of pile-supported bridges, thereby increasing the challenges in seismic design and maintenance of such bridges. This study focuses on widely built pile group supported highway girder bridges in sandy soil, considering various riverbed scour scenarios. The corresponding coupled site–foundation–bridge finite element (FE) model is developed in this study, considering the uncertainties in structural and soil parameters as well as the record-to-record variability. The FE model is then validated by comparing the shaking table test data. After that, the impact of scour on the key seismic response of bridges is investigated. Furthermore, based on the seismic fragility method, the seismic damage mechanism of pile group supported girder bridges under the combined effects of earthquake and scour is explored in a probabilistic manner. The research result shows that scour significantly affects the seismic demand of pile group supported bridges. As the scour depth increases, the seismic fragility of the potential plastic regions in the pile group gradually increases, while the damage probability of the piers tends to decrease. More importantly, the seismic damage location could shift from the pier and bearing to the pile group, making the pile group a vulnerable component. Under cyclic seismic loading, the below-ground plastic regions that form in an outer-row pile when it acts as the leading and trailing pile, respectively, may overlap, producing a total plastic-region length greater than that of the middle-row piles. As the scour depth increases, the embedded depths of the below-ground plastic region in pile shafts decrease. Under different damage probability levels, the damage sequence among the bearing, pier, and foundation differs. However, the damage sequence of potential plastic hinges within the pile group is consistent, with the order as follows: the pile head of the outer-row piles, the pile head of the middle-row piles, the pile shaft below the ground of the outer-row piles, and the pile shaft below the ground of the middle-row piles. This study can provide a reference for the seismic performance assessment, design, and retrofit of river-crossing highway bridges in China.