Using 137Cs and 210Pb dating and multi-proxy evidence from a 41-cm sediment core from Bosten Lake in China, the responses of sediment grain size to environmental changes were reconstructed over the past 150 years. After the end of the Little Ice Age, the climate of the Bosten Lake region became warmer and drier, and the lake water level decreased. The results indicated that the lowest water storage periods occurred at approximately 1920–1930 AD. Decreases in the Siberian High intensity and water vapour transport from the Indian Ocean during this period led to a reduction in the water vapour supply, which resulted in reduced lake levels in the period 1920–1930 AD. Then, the lake was at a high level until the 1960s. The water storage then declined in the 1960s. Since the 1960s, the contents of total organic carbon and total nitrogen have significantly decreased, which is closely related to the significant decline in water level and increased water salinity caused by enhanced water demands. Increased irrigation water demand as a result of expanding cultivated areas and climate change, coupled with a reduced input of water vapour, resulted in the worst water environment in approximately 1980–1990 AD. Since the late 1980s, the water level of the lake has risen, and the lake primary productivity of Bosten Lake has improved. Through the application of statistical methods to grain size data from Bosten Lake combined with the abovementioned data on climate change and human activities, two major potential factors influencing the grain size of terrigenous clastic material were revealed. The first factor, consistent with a grain size of 3.31 μm, is related to the recent increase in agricultural acreage in the Bosten Lake watershed and may reflect increases in atmospheric dust. The second factor, correlated with grain sizes of 11.48 μm and 69.18 μm, can be used to reflect changes in the lake hydrological state. It is suggested that the grain sizes of these lake sediments sensitively reflect changes in the hydrological characteristics of the basin and can be used to reconstruct the history of climate change and human activities.