Continental weathering regulates long-term climate via atmospheric CO2 consumption. Understanding how weathering regimes respond to tectonic and climatic forcing is therefore essential for clarifying the weathering-climate relationships. The Plio-Pleistocene reorganization of the Yellow River drainage provides an ideal setting to investigate such changes. While accumulating evidence suggests establishment of the modern-like drainage system no later than similar to 1 Ma, how this geomorphic transformation affected weathering patterns remains unexplored. Here, we address this question using new Li isotopic data (delta Li-7) from a marginal sea sediment core, integrated with Nd isotopes and geochemical records. Our multi-proxy record reveals a coupled provenance and weathering regime shift during the Mid-Pleistocene Transition (MPT). The epsilon Nd values shift from cratonic (-12 to -16) to orogenic (-10 to -12) signatures, while delta Li-7 values of weathering products transition from -2.7 +/- 0.9 parts per thousand to -0.9 +/- 0.6 parts per thousand. Combined with mineralogical and geochemical weathering indices, these data document a shift from more incongruent weathering dominated by continental margin floodplains to more congruent weathering governed by highlands of the NE Tibetan Plateau and Loess Plateau. We interpret this transition as a direct response to Yellow River reorganization, which replaced proximal cratonic sources with detritus from rapidly eroding orogenic and loess regions. Our study thus demonstrates that the balance between floodplain and mountain weathering set by large river drainage integration, maybe an important control on the type and intensity of silicate weathering over geologic timescales.