When and how the central Rocky Mountains (Rockies) of western North America gained modern topography remain controversial questions. We reconstruct the middle and late Cenozoic topography along a transect that extends from the Great Plains of western Nebraska across the central Rockies in Wyoming, based on reconstructed surface-water δD values from volcanic glass δD values. Our data show gradual increases of surface-water δD values in both the central Rockies and adjacent Great Plains during middle and late Cenozoic time, and the establishment of a similar-to-present surface-water δD gradient between the central Rockies and western Great Plains before earliest Oligocene time. These observations suggest that the region underwent differential uplift to form relief similar to that of today before earliest Oligocene time. This uplift has caused regional drying and the gradual increase of surface-water δD values over the past 35 m.y. When placed in the context of other paleoaltimetry studies, our work suggests that along our transect, the central Rockies and adjacent Great Plains underwent uplift during the late Eocene, and have not undergone any large-magnitude (>∼500 m) uplift since that time.