Active faults along railways in the mountainous regions of western China pose significant challenges to bridge safety. To ensure the safe operation of long-span railway bridges under complex geological conditions, this study investigates the synthesis of artificial ground motions for bridges crossing strike-slip faults and analyzes their nonlinear seismic response. First, we develop a theoretical method for simulating high- and low-frequency seismic motions using a finite fault and an equivalent velocity pulse model. Next, using a specific long-span railway cable-stayed bridge as a case study, we construct a nonlinear finite element model with OpenSees software. Finally, we assess the seismic response of key bridge components considering various crossing angles, seismic amplitudes, fault rupture directivity, and fling-step effects. The results show that the crossing angle significantly influences the seismic response, with longitudinal and transverse responses exhibiting opposite patterns. Additionally, the scaling factor of seismic motion significantly affects bridge response. For bridges crossing strike-slip faults, the longitudinal response exhibits a sudden increase in displacement due to instantaneous velocity pulses, while the transverse response shows notable residual displacement influenced by the fling-step effect. However, the critical section curvatures of bridge towers and piers remain within the elastic range across all crossing angles, indicating that controlling large displacement deformations is crucial for the seismic design of bridges crossing strike-slip faults.