Mineral dissolution rates in the critical zone (CZ) depend on physical, chemical, and biotic processes, although the means by which climate variations regulate the relative importance of these processes remain ambiguous. We analyzed trace-element and bulk chemical concentrations in a 50 k.y. sedimentary archive at our unglaciated, mid-latitude study area to show that glacial-interglacial transitions generate systematic and offsetting variations in chemical weathering intensity and denudation. The transition from cool and wet to colder and drier conditions prior to the Last Glacial (LG) coincides with a monotonic decline in chemical alteration, estimated by the chemical depletion fraction (CDF), and an increase in denudation rate, estimated from in situ10Be. During the cold and sparsely forested LG (29–14 ka), we observe low CDF values (<0.1) and rapid denudation (>0.22 mm yr–1), consistent with increased physical weathering and soil transport by periglacial processes. Conversely, slower denudation (∼0.1 mm yr–1) and higher CDF values (∼0.25) characterize the warm and densely vegetated late Holocene. These opposing trends in chemical depletion and denudation rate imply relatively consistent chemical weathering fluxes during Quaternary climate extremes, despite significant variations in temperature and vegetation. Additionally, our observations of weakly altered LG lake sediments and highly altered modern soils and shallow bedrock imply substantial post-LG alteration and deepening of the CZ. Our novel approach and results demonstrate how changes in the efficacy of abiotic and biotic processes modulate the CZ and reveal the influence of past climates on modern CZ characteristics.