The chemical weathering of rocks, in particular silicate weathering, has been proposed to be an important natural carbon-removal process that regulates the Earth’s climate over millions of years. Tectonically active regions, such as the sub-Himalayan region, are considered a hotspot of silicate weathering and key sites for understanding weathering processes. Rivers, as a carrier of eroded and weathered materials, provide a primary archive for the study of silicate weathering. This study focuses on one of the largest rivers draining from the Himalayan-Tibetan-Plateau region, the Mekong River. A major new data set is presented of the elemental abundance (major and trace) and isotopic composition (lithium-strontium-neodymium) for the suspended and bank/bedload particulates collected from depth profiles along the Mekong main channel and spot samples from tributaries. This includes the residues after leaching and a suite of sequential extractions targeting the exchangeable cation pool and Fe-Mn oxyhydroxide pool. In conjunction with the river sediments, new data on major elements and lithium isotopes in the dissolved load and from a sediment core of Tonle Sap, a lake connected to the Mekong, are also presented for comparison. The major conclusions from these data are:

1. The exchangeable and iron-manganese oxyhydroxide pools are too small to account for lithium fractionation between water and solids in the Mekong.
2. Chemical variations of suspended sediments along depths reflect a strong influence from hydrodynamic sorting and the downstream evolution of average sediment composition is attributable either to progressive chemical weathering or a change in the source material.
3. Lithium isotopes in the residues of Mekong sediments display no systematic trends with depth or grain size. If not an artefact from dams or agriculture, it might reflect a supply source different to the Mackenzie and Amazon, potentially dominated by more recent marine sediments, with a higher fraction of products from the modern weathering cycle.
4. Despite receiving sediments mainly from the Mekong River, the lake deposits are distinct from modern river sediments, which raises concerns about reconstructing weathering history from sediment cores.