Otherwise stable cratons periodically experience enigmatic episodes of large-scale uplift and subsidence that may result in widespread marine transgressions and the subsequent formation of sedimentary basins. Strata in the Western Canada Sedimentary Basin, for example, record flooding events that reached deep into the interior of the continent during the Devonian to Carboniferous. The epeirogenic motion which caused this deposition was contemporaneous with compressive tectonic events along the western plate margin of Laurussia. We propose that the long-wavelength component of inferred subsidence and uplift across the basin was the result of mantle flow-induced dynamic topography. In particular, we investigate the epeirogenic signals associated with the coupled mantle processes of near-surface subduction and later stage penetration of accumulated slab material through the endothermic phase change at 660 km depth. Numerical simulations of convection are presented to model the thermo-mechanical evolution of subduction in the mantle. The associated dynamic topography is initially characterized by tilting of the continental margin and submergence approximately 1000 km from the trench due to viscous effects associated with the subduction. A more extensive transgression onto the continental platform follows as accumulating slab material penetrates through the endothermic phase change. We argue that the predicted subsidence and uplift is broadly consistent with the inferred record of Devonian–Carboniferous epeirogeny across western Canada, and thus that the evolution of the Western Canada Sedimentary Basin may be intimately connected to mantle flow processes occurring contemporaneously beneath the craton.