Continental weathering is an important feedback on climate change. However, uncertainty remains regarding the sedimentary response and scale of this feedback, due to the sporadic preservation of in situ geologic evidence for weathering. We examined the United States Gulf of Mexico coast continental margin for a downstream sedimentary response to Paleogene climate changes. The Gulf Coast is a receiving basin for fluvial systems draining a large area of the North American continental interior. We sampled cores that penetrate the nearly continuous ∼1000-m-thick siliciclastic marginal marine Wilcox Group (Paleocene–Eocene) and Frio Formation (Oligocene). The Wilcox strata were deposited within the Rockdale delta system at the terminus of the paleo–Colorado River, an ∼1 × 106 km2 drainage. Mineralogical and geochemical alteration indices demonstrate that sediment within the paleo–Colorado catchment was generated under temperate–tropical weathering conditions during the late Paleocene, shifting to higher intensity (warmer) weathering conditions at the Paleocene-Eocene boundary, and reversing to lower intensity (cooler) conditions during the Oligocene. The indices track the global ocean δ18O curve across the Paleocene-Eocene transition and into the Oligocene, an indication that global climate and hinterland weathering in North America were coupled during the Paleogene, and that silicate weathering was an important feedback to climate change over a continental-scale, tectonically active catchment.