The processes initiating the first cooling step of the last greenhouse-to-icehouse transition, from 90 million years ago (Ma) onward still remain enigmatic. While the combination of mountain uplift and continental weathering has been proposed as a major sink for atmospheric CO2 and a climate driver over geological timescales, this hypothesis is much debated and its potential importance in triggering the late Cretaceous global cooling is yet to be explored. In this work, we combined clay mineralogy, trace and major element concentrations, and a new proxy of silicate weathering intensity based on Nd and Hf isotopes (∆ɛHf(t)clay) to explore the potential links between the uplift of the brazilian margin, silicate weathering and climate evolution during the late Cretaceous. Our new ∆ɛHf(t)clay proxy data suggest - for the first time - that marked increase of silicate weathering intensity occurred in southeast Brazil during the late Cretaceous, from ~85 to 70 Ma, related to the tectonic uplift affecting the eastern South American margin at that time. Combined with clay mineralogical analyses, our HfNd isotope data further suggests the existence of a relatively arid local climate during the Turonian-Santonian interval, during which physical disaggregation of rocks most likely prevailed, accompanying the uplift of the Brazilian margin. From the Santonian, we propose that the exposure of new high-elevation regions favored instead locally enhanced precipitations and more hydrolysing conditions, thereby promoting chemical weathering and atmospheric CO2 drawdown. Altogether, our multi-proxy investigation suggests that the uplift of the Brazilian margin could have contributed to the late Cretaceous cooling, potentially playing a key role in the onset of the last greenhouse-to-icehouse transition.