Antarctica’s continental margins pose an unknown submarine landslide-generated tsunami risk to Southern Hemisphere populations and infrastructure. Understanding the factors driving slope failure is essential to assessing future geohazards. Here, we present a multidisciplinary study of a major submarine landslide complex along the eastern Ross Sea continental slope (Antarctica) that identifies preconditioning factors and failure mechanisms. Weak layers, identified beneath three submarine landslides, consist of distinct packages of interbedded Miocene- to Pliocene-age diatom oozes and glaciomarine diamicts. The observed lithological differences, which arise from glacial to interglacial variations in biological productivity, ice proximity, and ocean circulation, caused changes in sediment deposition that inherently preconditioned slope failure. These recurrent Antarctic submarine landslides were likely triggered by seismicity associated with glacioisostatic readjustment, leading to failure within the preconditioned weak layers. Ongoing climate warming and ice retreat may increase regional glacioisostatic seismicity, triggering Antarctic submarine landslides.