<p>The Guantan landslide, with an estimated volume of 4.68 × 10⁶ m³, was one of the most catastrophic mass movements triggered by the 2008 Wenchuan earthquake. The landslide deposit dammed the river, forming a barrier lake that posed severe threats to downstream populations and infrastructure. Unlike many earthquake-induced landslides, the Guantan landslide developed within an anti-dip slope structure underlain by a weak mudstone layer, drawing particular attention. However, the dynamic responses and failure mechanisms of such weak-base anti-dip slopes under seismic loading remain insufficiently understood. This study combines field investigations, shaking table experiments, and discrete element numerical simulations to examine the deformation and failure processes of the Guantan slope. Shaking table tests demonstrate that under seismic loading, peak rock pressure within the mudstone is significantly higher than in the adjacent dolomite, with the highest values near the slope surface. Numerical results reveal a four-stage failure process: compressive deformation of mudstone under gravity, seismic-induced cracking in mudstone and tensile–shear fracture development in dolomite, crack coalescence leading to a continuous slip surface, and rainfall infiltration and softening-induced failure. The study highlights that incompatible deformation amplifies tensile–compressive and shear stresses within the mudstone layer. A near-surface rocking effect causes transient stress concentration, promoting damage. These penetrating cracks accelerate rainfall infiltration and mudstone softening, ultimately destabilizing the slope. This integrated analysis enhances our understanding of the seismic failure mechanisms of anti-dip slopes with weak bases.</p>