High-resolution siliciclastic grain size and bulk mineralogy combined with clay mineralogy, rubidium, strontium, and neodymium isotopes of Core MD01-2393 collected off the Mekong River estuary in the southwestern South China Sea reveals a monsoon-controlled chemical weathering and physical erosion history during the last 190,000 yr in the eastern Tibetan Plateau and the Mekong Basin. The ranges of isotopic composition are limited throughout sedimentary records: 87Sr/86Sr = 0.7206–0.7240 and ε
Nd(0) = −11.1 to −12.1. These values match well to those of Mekong River sediments and they are considered to reflect this source region. Smectites/(illite + chlorite) and smectites/kaolinite ratios are used as indices of chemical weathering rates, whereas the bulk kaolinite/quartz ratio is used as an index of physical erosion rates in the eastern Tibetan Plateau and the Mekong Basin. Furthermore, the 2.5–6.5 μm/15–55 μm siliciclastic grain size population ratio represents the intensity of sediment discharge of the Mekong River and in turn, the East Asian summer monsoon intensity. Strengthened chemical weathering corresponds to increased sediment discharge and weakened physical erosion during interglacial periods. In contrast, weakened chemical weathering associated with reduced sediment discharge and intensified physical erosion during glacial periods. Such strong glacial–interglacial correlations between chemical weathering/erosion and sediment discharge imply the monsoon-controlled weathering and erosion.