The runoff levels of the major hydrological stations in the Weihe river basin (WRB) have been found to present decreasing trends. However, the conspicuous spatial differences in the hydro-meteorological conditions have led to variations in the rainfall–runoff pattern in each of the sub-basin areas. The aims of this research study were to reveal the main factors contributing to the runoff changes in the different regions—and it has significance in the water resources rational allocation and protection in the different regions. Three statistical methods were used to analyze the law of precipitation and runoffs of five hydrological stations. The SWAT (Soil and Water Assessment Tool) model was used to reconstruct the runoff in the impact period. The effects of climate change and human activity on runoff were separated by comparing measured runoff and reconstructed runoff. The results show that the closer the proximity to the downstream hydrological station, the more the runoff decreased. In the tributaries and upstream hydrological stations (Zhuanhtou (ZT), Zhangjiashan (ZJS), and Linjiacun (LJC)), from 1970 to 2016, the dominant factor of the runoff reduction was determined to be climate change, and accounted for 148.2%, 98.9%, and 90.5%, respectively. In the hydrological stations of middle and lower reaches (Xianyang (XY) and Huaxian (HX)), the contributions of the climate change to the runoff reduction were 49.7% and 44.3%, respectively, and the impacts of human activity accounted for 50.3% and 55.7%. The impacts of human activity on the runoff reduction were slightly greater than that of the climate change. Due to the different leading factors affecting runoff change in the basin, in response to future climate change, for tributaries and upstream areas, land use should be rationally planned to achieve the optimal balance of water volume in each part of the basin, which is of great significance to the protection and utilization of water resources. As for the middle and downstream regions, reasonable planning should also be focused on the amount of water withdraw, water resource allocations, and water conservancy project construction. According to the factors affecting runoff, corresponding strategies are proposed for different regions, which have important research significance for the protection and sustainable development of watershed water resources.