Understanding the causes of intraplate earthquakes is challenging, as it requires extending plate tectonic theory to the dynamics of continental deformation. Seismicity in the western United States away from the plate boundary is clustered along a meandering, north-south trending 'intermountain' belt(1). This zone coincides with a transition from thin, actively deforming to thicker, less tectonically active crust and lithosphere. Although such structural gradients have been invoked to explain seismicity localization(2,3), the underlying cause of seismicity remains unclear. Here we show results fromimproved mantle flowmodels that reveal a relationship between seismicity and the rate change of 'dynamic topography' (that is, vertical normal stress from mantle flow). The associated predictive skill is greater than that of any of the other forcings we examined. Wesuggest that active mantle flow is amajor contributor to seismogenic intraplate deformation, while gravitational potential energy variations have a minor role. Seismicity localization should occur where convective changes in vertical normal stress are modulated by lithospheric strength heterogeneities. Our results on deformation processes appear consistent with findings from other mobile belts(4), and imply that mantle flow plays a significant and quantifiable part in shaping topography, tectonics, and seismic hazard within intraplate settings.