Abstract: A dynamic model of the “mechanism-structure” stacked multi-body system, incorporating wheel-rail contact, is established for a stacked system comprising the containment vessel and a polar crane at nuclear island. The derailment mechanism under the coupled effects of horizontal and vertical seismic actions, along with its influence on floor response spectrum, is systematically investigated. The simulation results reveal that the detachment behavior of the stacked components is governed by the combined effects of the structure’s dynamic characteristics and seismic properties. The excessive compression of horizontal isolators is identified as a critical factor in inducing detachment. Furthermore, the crane, characterized by a small rotational inertia about its longitudinal symmetry axis, is shown to be particularly susceptible to swaying motion under transverse seismic loading. The abrupt return motion associated with strong horizontal earthquakes is found to initiate relative sliding between the wheel and rail, while the corresponding motion from strong vertical earthquakes further diminishes the amplitude of the wheel-rail contact force. This reduction weakens frictional resistance, intensifies horizontal impact, and ultimately precipitates derailment. The substantial impact force generated by derailment is observed to excite high-frequency vibrations within the containment, resulting in pronounced peaks in the floor response spectrum during short periods, with spectral amplitudes increasing with elevation. These findings are demonstrated to offer valuable theoretical insights for the aseismic design of stacked systems in nuclear power plants.