Climate change and land use/cover change (LUCC) are two major factors that alter hydrological processes. The upper reaches of the Tarim River, situated in the northwest region of China, experience a dry and less rainy climate and are significantly influenced by human activities. This study comprehensively assessed the impacts of individual and combined climate changes and LUCCs on streamflow. Three general circulation models (GCMs) were utilized to predict future climate changes under three shared socioeconomic pathways (SSP119, SSP245, and SSP585). Cellular Automata–Markov (CA–Markov) was employed to predict future LUCC under three scenarios (i.e., ecological protection, historical trend, and farmland development). Streamflow for the period 2021–2050 was simulated using the calibrated MIKE SHE model with multiple scenarios. The results showed that from 2021 to 2050, increments in both average annual precipitation and average annual temperature under the three SSPs were predicted to lead to an increased streamflow. In comparison to the conditions observed in 2000, under three LUCC scenarios for 2030, the grassland area decreased by 1.04% to 1.21%, while the farmland area increased by 1.97% to 2.26%, resulting in reduced streamflow. The related changes analysis indicated that the variation in streamflow during winter is most significant, followed by spring. The study predicted that climate change would increase streamflow, while LUCC would decrease it. Due to the greater impact of LUCC, considering the combined effect of both factors, runoff would decrease. The contribution analysis indicated that climate change contributed between −7.16% and −18.66%, while LUCC contributed between 107.16% and 118.66%.