Although the timing of an acceleration in late-Cenozoic exhumation of southern Alaska is reasonably well constrained as beginning ∼5–∼6 Ma, the surface uplift history of this region remains poorly understood. To assess the extent of surface uplift relative to rapid exhumation, we developed a stable isotope record using the hydrogen isotope composition (δD) of paleo-meteoric water over the last ∼7 Ma from interior basins of Alaska and Yukon Territory. Our record, which is derived from authigenic clays (δDclay) in silicic tephras, documents a ∼50–60‰ increase in δD values from the late Miocene (∼6–∼7 Ma) through the Plio-Pleistocene transition (∼2–∼3 Ma), followed by near-constant values over at least the last ∼2 Ma. Although this enrichment trend is opposite that of a Rayleigh distillation model typically associated with surface uplift, we suggest that it is consistent with indirect effects of surface uplift on interior Alaska, including changes in aridity, moisture source, and seasonality of moisture. We conclude that the δDclay record documents the creation of a topographic barrier and the associated changes to the climate of interior Alaska and Yukon Territory.