<p>During seismic events, imposing speed restrictions on vehicles crossing bridges often serves as the last line of defense for operational safety. However, the relative spatial relationship between fault and bridge, coupled with the fling-step and forward-directivity effects, presents significant challenges in determining speed limits for vehicles under strike-slip faulting. To address this issue, this study develops a nonlinear coupled vehicle-bridge model with the adoption of non-uniform seismic excitation input method to systematically investigate the impact of strike-slip faulting on safe running speeds. The study analyzes 264 computational cases, incorporating two spatial parameters—Fault-Bridge Angle (FBA) and Fault-Crossing Position (FCP)—along with synthesized permanent displacement to comprehensively characterize the distinctive effects of strike-slip faulting. Furthermore, a novel speed-limit assessment framework employing the geometric derailment criterion is proposed for vehicles on simply-supported bridges subjected to strike-slip faulting. Within the scope of this study and based on the four typical strike-slip faulting records, the results reveal pronounced angular and positional dependencies in both structural and vehicular responses, with derailment risk increasing as vehicle speed rises and the FBA approaches 90°. Additionally, permissible running speed limits are found to vary significantly based on spatial parameters, with a trend toward higher allowable speeds at larger FBAs. These findings offer valuable insights for the seismic design and operational safety of railway simply-supported bridges in active fault zones.</p>