Patterns of late Palaeogene mammalian evolution appear to be very different between Eurasia and North America. Around the Eocene-Oligocene (EO) transition global temperatures in the Northern Hemisphere plummet: following this, European mammal faunas undergo a profound extinction event (the Grande Coupure), while in North America they appear to pass through this temperature event unscathed. Here, we investigate the role of surface uplift to environmental change and mammalian evolution through the Palaeogene (66-23 Ma). Palaeogene regional surface uplift in North America caused large-scale reorganization of precipitation patterns, particularly in the continental interior, in accord with our combined stable isotope and ecometric data. Changes in mammalian faunas reflect that these were dry and high-elevation palaeoenvironments. The scenario of Middle to Late Eocene (50-37 Ma) surface uplift, together with decreasing precipitation in higher-altitude regions of western North America, explains the enigma of the apparent lack of the large-scale mammal faunal change around the EO transition that characterized western Europe. We suggest that North American mammalian faunas were already pre-adapted to cooler and drier conditions preceding the EO boundary, resulting from the effects of a protracted history of surface uplift.