The Ancestral Rocky Mountains (ARM) formed a system of highlands and adjacent basins that developed during Pennsylvanian–earliest Permian deformation of interior western North America. The cause of this intracratonic deformation remains debated, although many have linked it to far-field compression associated with the Carboniferous–Permian Ouachita-Marathon orogeny of southern North America. The ultimate disappearance of the ARM uplifts has long been attributed to erosional beveling presumed to have prevailed into the Triassic–Jurassic. New observations, however, indicate an abrupt and unusual termination for the largest of the ARM uplifts. Field evidence from paleohighlands in the central ARM of Oklahoma and Colorado indicates that Lower Permian strata onlap Pennsylvanian-aged faults and bury as much as 1000 m of relief atop the paleohighlands. In parts of Oklahoma and Colorado, late Cenozoic partial exhumation of these paleohighlands has revealed landscapes dating from Permian time. These relationships suggest cessation of uplift followed by active subsidence of a broad region that encompassed both basins and uplifted crustal blocks and that commenced in Early Permian time, directly following the Pennsylvanian tectonic apogee of the ARM. Independent from these geological observations, geophysical data reveal a regional-scale mafic load underpinning these paleohighlands, emplaced during Cambrian rifting associated with the southern Oklahoma aulacogen. Geophysical modeling of the effects of such a load in the presence of a horizontal stress field, such as that implied by ARM orogenesis, indicates that the amplitude of flexurally supported features is modulated nonlinearly. This leads to buckling and thrust formation with the application of sufficient compressive stress, and subsidence of topography formed by buckling upon relaxation of the high compressional stresses. We therefore infer that the core ARM highlands subsided owing to the presence of a high-density upper crustal root, and that this subsidence began in the Early Permian owing to relaxation of the in-plane compressional stresses that had accompanied the last phase of the Ouachita-Marathon orogeny of southern and southwestern Laurentia. Our results highlight the importance of tectonic inheritance in intraplate orogenesis and epeirogenesis, including its potential role in hastening the reduction of regional elevation, and enabling the ultimate preservation of paleolandscapes.