Abstract: A large number of hazardous rock masses are distributed in Southwest China, which are highly susceptible to collapse under earthquake action. Through large-scale shaking table model tests, this study investigated the instability failure modes and acceleration responses of hazardous rock masses subjected to different seismic wave loading directions and amplitudes. Theoretical equations for the critical deflection angle leading to collapse instability were also derived and subsequently validated. The test results indicate that under horizontal seismic loading, the predominant failure mode is toppling. In contrast, when seismic waves are applied at a 45° angle to both the horizontal and vertical directions, the failure mode is characterized by a combination of sliding and toppling. The acceleration responses under the two loading directions exhibit the following characteristics: as the slope elevation increases, the peak ground acceleration (PGA) amplification factor increases significantly for both loading directions, and the overall trend of the amplification factor curves is largely similar. However, the amplification factor values are consistently larger under purely horizontal loading than under the mixed-direction loading. Furthermore, for a given loading direction, the PGA amplification factor increases with increasing loading amplitude. Different seismic wave loading directions lead to distinct failure modes and marginally different critical deflection angles. Theoretical calculations show that the critical deflection angle for toppling failure is 34.28°, whereas the critical angle for the mixed sliding-toppling failure mode needs to be determined by considering both horizontal and vertical displacements. The analytical results are in good agreement with the experimental observations, further revealing the effects of varying loading directions and amplitudes on the instability failure modes and acceleration responses of critical rock masses under strong seismic actions.