Climate change and land use/cover change (LUCC) have been widely recognized as the main driving forces that can affect regional hydrological processes, and quantitative assessment of their impacts is of great importance for the sustainable development of regional ecosystems, land use planning and water resources management. This study investigates the impacts of climate change and LUCC on variables such as streamflow (SF), soil moisture (SM) and evapotranspiration (ET) in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) by using Soil and Water Assessment Tools (SWAT) model under different scenarios during 1979–2018. The results show that the simulation performances were overall good, with Nash-Sutcliffe Efficiency Coefficient (NSE) and coefficient of determination (R2) greater than 0.80 for the monthly-scale SF calibration and validation. According to the results of trend and change point tests of meteorological series, the baseline period (1979–1997) and the interference period (1998–2018) were determined. Interestingly, other land use types were basically converted to urban land, leading to a rapid urbanization in the GBA. Compared with the SF values of the eight estuaries of the Pearl River Basin in the baseline period, both climate change and LUCC has led to the decrease in the SF values in the interference period, and the combined effect of climate change and LUCC was slightly greater than their individual effect. Overall, climate change and LUCC both have important impacts on regional hydrological processes in the GBA.