We aim to determine the intensity of chemical weathering of detrital clays, as well as the lag time between the onset of the Paleocene-Eocene Thermal Maximum (PETM) and the chemical weathering response in a source-to-sink system. The PETM was a hyperthermal event characterized by an abrupt increase in global temperature (5–8 °C) over a short period (20 ka). A negative carbon isotope excursion marks the onset of the PETM, which reflects the fast injection of light carbon into the ocean-atmosphere system, triggering global climatic changes. Thus, physical and chemical erosion acted as feedback mechanisms to recover the global climate to pre-onset conditions. We focus on the continental section of the source-to-sink system, near the locality of Esplugafreda in the Southern Pyrenean foreland basin. We analyzed the evolution of the clay mineral assemblages in two clay-sized fractions (<0.5 µm and <2 µm), which can provide insights into the hydrolyzing conditions on the continents. We then measured oxygen and hydrogen stable isotopes as indicators of paleo-precipitation, temperature, and elevation of the catchment areas. The clay mineralogy results show an interplay of reworked clays during the extreme events, together with more hydrolyzing conditions marked by the production of authigenic clay during the onset and body of the PETM. The stable isotope geochemistry results point towards a climatically controlled response, where temperature fluctuations, as opposed to precipitation, played the main role in shaping the climatic regime. This is evidenced in a negative δ¹⁸O excursion at the onset and body of the PETM found in both size fractions. Further, we combine hafnium and neodymium isotope analyses of both clay fractions to track the silicate weathering intensity. This method will help us constrain the weathering regime and its response time relative to the onset and the body of the PETM. The results obtained in this project will serve to test numerical models of landscape evolution incorporating the chemical weathering response to climatic changes. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 860383.