AbstractHigh‐elevation, low‐relief continental plateaus are major topographic features and profoundly influence atmospheric circulation, sediment transport and storage, and biodiversity. Although orogenic surface‐uplift mechanisms for modern continental plateaus near known plate margins like Tibet are well‐characterized, they cannot account for examples in intracontinental settings like the Colorado Plateau. In contrast to canonical plate‐tectonic uplift mechanisms, broad‐scale hydration‐induced metasomatism of the lower crust has been suggested to reduce its density and increase its buoyancy sufficiently to contribute to isostatic uplift. However, the relationships between key petrophysical properties in these environments are not fully quantified, which limits application of this model. Here, we develop a series of petrological models that describe the petrological and topographic effects of fluid–rock interaction in non‐deforming continental crust of varying composition. We apply an open‐system petrological modelling framework that utilizes reactive‐transport calculations to determine the spatial and temporal scales over which mineralogic transformations take place compared with the magnitude of infiltration of aqueous fluids derived from devolatilization of subducting oceanic lithosphere. The buoyancy effect of hydration‐induced de‐densification is most significant for metabasic lower crust, intermediate for metapelitic crust, and minimal for granodioritic crust. We apply these results to a case study of the ~2 km‐high Colorado Plateau and demonstrate that under ideal conditions, hydration of its lower–middle crust by infiltrating aqueous fluids released by the Farallon slab during Cenozoic low‐angle subduction could have uplifted the plateau surface by a maximum of ~1 km over 16 Myr. However, realistically, although hydration likely has a measurable effect on surface tectonics, the uplift of orogenic plateaus is likely dominantly controlled by other factors, such as lithospheric delamination.