Hydrological cycle is sensitively affected by climatic variation and human activity. Taking the upper- and middle-stream of the Weihe River in western China as an example, using multiple meteorological and hydrological elements, as well as land-use/land-cover change (LUCC) data, we constructed a sensitivity model of runoff to climatic elements and human activities based on the hydro-thermal coupling equilibrium equation, while a cumulative slope was used to establish a comprehensive estimation model for the contributions of climatic variation and human activities to the changes of runoff. The results showed that the above function model established could be well applied to quantitatively study the elasticity of runoff’s response to climatic variation and human activities. It was found that the annual average precipitation, evaporation, wind velocity, sunshine hours, relative humidity and runoff showed decreasing trends and that temperature increased. While in the hydrological cycle, precipitation and relative humidity had a non-linear positive driving effect on runoff, while temperature, evaporation, sunshine hours, wind velocity, and land-use/land-cover change (LUCC) have non-linearly negatively driven the variation of runoff. Moreover, runoff has a strong sensitive response to precipitation, evaporation and LUCC. In areas with strong human activities, the sensitivity of runoff to climatic change was decreasing, and runoff has a greater elastic response to underlying surface parameters. In addition, the analysis showed that the abrupt years of climate and runoff changes in the Weihe River Basin were 1970, 1985 and 1993. Before 1985, the contribution rate of climatic variation to runoff was 68.3%, being greater than that of human activities to runoff, and then the contribution rates of human activities to runoff reached 75.1%. The impact of natural climate on runoff was weakened, and the effect of human activities on runoff reduction increased. Under 30 hypothetical climatic scenarios, the evaluation of runoff in the future showed that the runoff in the Weihe River Basin will be greatly reduced, and the reduction will be more significant during the flood season. Comparing the geographically fragile environments and intense human activities, it was believed that climatic variation had a dramatic effect on driving the water cycle of precipitation and evaporation and affected regional water balance and water distribution, while human activities had driven the hydrological processes of the underlying surface, thus becoming the main factors in the reduction of runoff. This study provided scientific tools for regional climate change and water resources assessment.