[Objective] The contribution rates and composition of each factor in runoff depth were quantified to analyze the contribution rates of underlying surface, climate, and industrial and agricultural water use change to runoff change in the source region of the Yellow River, in order to provide references for ecological environment protection and water resource development in the Yellow River basin. [Methods] Based on the meteorological and hydrological data of the source region of the Yellow River from 1970 to 2021, the distributed water-heat coupled model WEP-ISF was used to analyze the dynamic changes in monthly average flow, actual evapotranspiration, soil temperature, soil moisture content and runoff components in different periods in the source region of the Yellow River, and the multi-factor attribution analysis method was used to quantitatively analyze the contribution of each influencing factor to the variation in runoff volume. [Results] ① Simulation and verification of the hydrological and water-heat change process in the source region of the Yellow River from 1970 to 2021 by using the WEP-ISF model showed that the average absolute percentage error between the simulated soil temperature and remote sensing interpreted value was between 69.78% and 171.55%, and the Nash efficiency coefficient was more than 0.70; the average absolute percentage error between the simulated surface soil moisture content and remote sensing interpreted value was between 13.94% and 20.97%, and the Nash efficiency coefficient was more than 0.5; the Nash efficiency coefficient and average absolute percentage error between the simulated monthly average flow and measured value were 0.80 and 25.85%, respectively; and the Nash efficiency coefficient and average absolute percentage error between the simulated actual evapotranspiration and remote sensing interpreted value were 0.80 and 53.39%, respectively. ② The multi-year average runoff from glaciers, snowmelt, and precipitation in the source region of the Yellow River was 0.9, 14.9, and 70.5 mm, accounting for 1.0%, 17.3%, and 81.7%, respectively, of the runoff depth in the source region of the Yellow River. Compared with the baseline period of 1970—1990, the change in runoff from glaciers, snowmelt and precipitation during the change period of 1991—2021 was 1.48, -3.8, and -13.2 mm, respectively, accounting for 9.53%, -24.48%, and -85.05%, respectively, of the change in the runoff depth of the source region of the Yellow River. ③ The multi-year average runoff at Tangnaihai decreased by 6.77×109 m3, among which the contribution rates of climate, underlying surface, and industrial and agricultural water use changes were 96.46%, 2.49%, and 1.05%, respectively. [Conclusion] Among the many factors affecting runoff change in the source region of the Yellow River, climate is the main driving factor leading to runoff attenuation, which is manifested in the trend of increasing glacier melt water flow and decreasing trend of snowmelt runoff and runoff.