In a tsunami disaster, long-span bridges in coastal areas form critical transport channels for relief so it is crucial that they survive tsunami wave forces. Here we establish a dynamic response analysis framework for long-span bridges and applied it to a landslide tsunami scenario impacting a sea-crossing cable-stayed bridge near Hong Kong, China. First, a meshless numerical approach called Tsunami Squares (TS) simulated the movement of a plausible submarine landslide and its generated near-source waves. Second, we propagated the tsunami ∼300 km to the bridge site and computed wave forces on the bridge substructure. Third, we constructed a dynamic response analysis of the long-span bridge due to those forces. Results show that transverse and longitudinal forces on the bridge substructure reach maximum at different times and transverse load is larger than longitudinal load. The transverse displacement of the cable-stayed bridge dominates both longitudinal and torsional displacements but falls below the safety level even under the most extreme tsunami conditions. Landslide features have non-linear effects on tsunami waves and structural responses so a wide parameter space should be considered. The framework developed here provides effective means for assessing the dynamic state of long-span bridges during tsunami disasters.