Isostatic surface uplift of large continental regions lacking deformation remains largely unexplained. Evidence from the eastern parts of the Cordilleran orogen in the western United States suggests that increased buoyancy in the lower crust supports the elevations of the High Plains and Wyoming craton. We suggest that hydration of the lower crust associated with the Laramide orogeny produced surface uplift by replacing dense mineral phases such as garnet with less dense phases such as amphibole and mica. Seismic and petrologic evidence from Wyoming and Montana is consistent with such changes. Comparable hydration in the Colorado Plateau is dated to the early Tertiary. Beyond establishing a newly recognized mechanism for broad continental uplift, such hydration suggests that interactions of subduction-derived fluids and the lithosphere can be more profound than previously envisioned.