The Cenozoic erosion history of the Himalaya-Karakoram, which is a function of tectonically driven uplift and monsoon climatic evolution in South Asia, remains elusive, especially prior to the Miocene. Here, we present a multiproxy geochemical and thermochronological analysis of the oldest samples available from the Arabian Sea, which we used to investigate the erosion history of the Himalayan and Karakoram orogenic system. The Indus Fan records rapid and sustained erosion of the Himalayan-Karakoram mountains from before 24 Ma (ca. 30) to ca. 16 Ma concurrent with changing provenance from the Indian (Himalayan) and Eurasian plates. Our data, combined with previous studies of younger Indus Fan deposits, indicate that the mid-to-late Cenozoic erosion history of the Himalayan-Karakoram mountains is overall consistent with a vigorous monsoonal climate from the late Oligocene to middle Miocene and with changes in global climate in the late Miocene, whereas erosion and deposition are relatively insensitive to changes in sources and rock erodibility. Although tectonic processes were active throughout, we suggest that the erosional signatures of the Himalayan-Karakoram mountains from the Indus Fan largely preserve a record of climate changes since the Oligocene.