The origin and antiquity of the subdued topography of the Yukon–Tanana Upland (YTU), the physiographic province between the Denali and Tintina faults, are unresolved questions in the geologic history of interior Alaska and adjacent Yukon. We present apatite fission-track (AFT) results for 33 samples from the 2300 km2 western Fortymile district in the YTU in Alaska and propose an exhumation model that is consistent with preservation of volcanic rocks in valleys that requires base level stability of several drainages since latest Cretaceous–Paleocene time. AFT thermochronology indicates widespread cooling below ∼110 °C at ∼56–47 Ma (early Eocene) and ∼44–36 Ma (middle Eocene). Samples with ∼33–27, ∼19, and ∼10 Ma AFT ages, obtained near a major northeast-trending fault zone, apparently reflect hydrothermal fluid flow. Uplift and erosion following ∼107 Ma magmatism exposed plutonic rocks to different extents in various crustal blocks by latest Cretaceous time. We interpret the Eocene AFT ages to suggest that higher elevations were eroded during the Paleogene subtropical climate of the subarctic, while base level remained essentially stable. Tertiary basins outboard of the YTU contain sediment that may account for the required >2 km of removed overburden that was not carried to the sea by the ancestral Yukon River system. We consider a climate driven explanation for the Eocene AFT ages to be most consistent with geologic constraints in concert with block faulting related to translation on the Denali and Tintina faults resulting from oblique subduction along the southern margin of Alaska.