Silicate weathering regulates Earth’s long-term climate by removing atmospheric CO2. Understanding changes in weathering regimes and rates is key to predicting climate response time scales. We investigated the reactivity of the North American source-to-sink system and the chemical weathering regime during the Paleocene–Eocene Thermal Maximum (PETM). We measured the detrital lithium isotope composition (δ7Li) in a deep-marine sediment core from the Gulf of Mexico, tracking changes in the formation of clay minerals, alongside neodymium isotopes (εNd), to constrain sediment provenance. We find a buffered negative δ7Li excursion during the PETM body, likely reflecting the mixing of neoformed and reworked clays from continental floodplains, followed by a stronger negative δ7Li excursion during the recovery phase. This pattern aligns with the continental Bighorn Basin (Wyoming, USA) δ7Li record, indicating rapid propagation of enhanced weathering and erosion fluxes in response to the PETM, which would have contributed to efficient CO2 drawdown.