Colorado’s High Plains stand at anomalously high elevations (~1300–2100 m) for their continental interior setting, but when and why this region became elevated is poorly understood. The Cenozoic history of the High Plains is also likely linked with that of the Rocky Mountains, where the timing and cause(s) of uplift are similarly debated. We present apatite (U-Th)/He (AHe) data for 10 samples from Tertiary intrusives along a ~200 km west-to-east transect across the High Plains of southeastern Colorado to constrain the timing of exhumation and to gain insight into when and why regional elevation gain occurred. Mean sample AHe dates for the ~24–22 Ma East Spanish Peak pluton and associated radial dikes from the westernmost High Plains are 18.8 ± 1.4 to 14.1 ± 1.7 Ma, recording substantial postemplacement erosion. AHe results for the mafic to ultramafic Apishapa Dikes (oldest ~37 Ma, youngest ~14 Ma) located ~20–40 km farther north and east on the High Plains range from 12.0 ± 1.4 to 6.2 ± 1.9 Ma, documenting continued exhumation on the western High Plains during the ~12–5 Ma deposition of the Ogallala Formation farther east and suggesting that the western limit of Ogallala deposition was east of the Apishapa Dikes. In far southeastern Colorado, the Two Buttes lamprophyre was emplaced at 36.8 ± 0.4 Ma and yields a Late Oligocene AHe date of 27.1 ± 4 Ma. Here, the Ogallala Formation unconformably overlies Two Buttes, indicating that the regional ~12 Ma age for the base of the Ogallala is a minimum age for the exposure of the pluton at the surface. The AHe data presented here document that kilometer-scale erosion affected all of the southeastern Colorado High Plains in Oligo-Miocene time. While exhumation can have multiple possible causes, we favor contemporaneous surface uplift capable of elevating the region to modern heights.