Landslide-induced tsunamis pose a significant yet underrecognized hazard in lake-rich, tectonically active regions such as south-central Chile. This study reconstructs and numerically models two contrasting tsunamigenic landslide scenarios in Lake Rupanco: (i) a multi-source subaerial landslide triggered by the 1960 Valdivia earthquake (Mw 9.5), and (ii) a large, deep-seated paleo-landslide inferred from geomorphological and bathymetric evidence. Field surveys, historical imagery, and a high-resolution topo-bathymetric dataset were used to define landslide geometries and initial conditions. Simulations were performed using the Landslide-HySEA model, calibrated through a global sensitivity analysis to constrain key rheological parameters. The 1960 scenario generated peak wave amplitudes of up to 33.3 m, while the paleo-landslide produced waves reaching 22.0 m. Both events resulted in run-up heights exceeding 10 m and inundation distances over 200 m along the lake’s eastern and southern shores. The results demonstrate that landslide dynamics—not just volume—are critical in tsunami generation, and highlight the importance of integrating both historical and paleo-events into hazard assessments for confined water bodies in seismically active settings.