Located in the foreland domain of the Alpine and Pyrenean mountain belts, the French Massif Central presents enigmatic topographic features—reaching elevations of ∼1700 m above sea level and ∼1000 m of relief—that did not originate from Alpine compressional nor from extensional tectonics. Similar to other Variscan domains in Europe, such as the Bohemian, Rhenish, and Vosges/Black Forest Massifs, a Cenozoic uplift has been postulated, although its timing and quantification remain largely unconstrained. With respect to the other Variscan Massifs, the French Massif Central is wider and higher and shows a more intense late Cenozoic volcanism, suggesting that deep-seated processes have been more intense. In this study, apatite fission-track and (U-Th)/He thermochronometry were applied to investigate the long-term topographic evolution of the Massif Central. Our new thermochronological data come from the eastern flank of the massif, where sampling profiles ran from the high-elevation region down to the Rhône River valley floor with a total elevation profile of 1200 m. Age-elevation relationships, mean track-length distributions, and thermal modeling indicate a two-step cooling history: (1) a first exhumation event, already detected through previously published thermochronology data, with an onset time during the Cretaceous, and (2) a more recent Cenozoic phase that is resolved from our data, with a likely post-Eocene onset. This second erosional event is associated with relief formation and valley incision possibly induced by a long-wavelength domal uplift supported by mantle upwelling.