[Objective] Taking the upper reaches of Huaihe River basin as a case study, this paper investigates the law of runoff and its response to climate-driven factors in order to provide the scientific basis for flood control, reasonable planning of water resources and economic sustainable development.[Methods] By using hydrological statistics, cross wavelet transform analysis and elastic coefficient method, we analyzed the variation trend and the periodicity of the runoff in Huaihe River. The relation between the meteorological factors and the runoff in multi-time scales was analyzed as well in the study area.[Results] ① The runoff and precipitation exhibited a decreasing trend at a rate of -3.8 m³/(s·10 a) and -26.3 mm/10 a, respectively. The variation of potential evapotranspiration was not obvious. Precipitation was the most dominant factor controlling changes of annual runoff, and the correlation coefficient was 0.9 between precipitation and runoff. However, both precipitation and potential evapotranspiration influenced runoff processes within a year. ② Wavelet analysis showed that periodic variation of annual runoff in the upper reaches of Huaihe River was 6~12 a. The variation of precipitation and potential evapotranspiration presented a same periodicity of 2 a. There were significant correlations among annual-runoff, annual-precipitation and annual-potential evapotranspiration in 1990s. ③ The responses of runoff to climate-driven factors were not stable, changing with time. Elastic coefficient of annual precipitation and evapotranspiration were 2.30 and -0.47, respectively. Annual runoff had a significant correlation with precipitation while little correlation with the potential evaporation, indicated that precipitation change was the main factor that influence variation of water resources in future.[Conclusion] With the comprehensive impacts of climate change, underlying surface of watershed and human activities, the annual distribution of runoff uniformity will be changed greatly.