[Objective] The variation characteristics of runoff and its driving factors in the past 50 years in the middle area of Hexi corridor in Gansu Province were analyzed to provide a scientific basis for the ecological construction and the sustainable development of social economy. [Methods] Based on runoff data in the study area, the characteristics of the inter-annual variability of runoff were reflected with annual extreme value ratio and coefficient of variation, and other statistics methods. [Results] (1) The distribution of the runoff showed an unimodal type in the middle area of Hexi region. The proportion was the highest in summer, and it was the lowest in winter. The runoff mainly was sourced from precipitation. (2) The runoff had a decreasing trend in recent years, and the change of hydrologic characteristic was positively correlated with elevation. The annual average runoff had a reducing trend and then gradually became an increasing trend from the west to the south. (3) The mutation characteristics of the annual runoff was poor consistent in the middle of the Hexi region and inter-annual variability of the annual runoff had a characteristic of multi-scale oscillation. The fluctuation had a quasi-cycle obviously in 8 a and 24 a, and the quasi-cycle in 8 a was more obvious, whereof 13 cycles as“much-less-much-less…”were observed. The runoff reduced after 2010, and might increase in 2018. (4) Runoff was both affected by the increase of temperature and precipitation, while was little affected by human activity. [Conclusion] Runoff is mainly supplied by precipitation in the study area. The changes were smaller in the past nearly 50 years. The annual average runoff had a reducing trend and then gradually became an increasing trend from the west to the south, and had a strongest quasi-cycle obviously in 8 a. Temperature and rainfall are the two main causes of runoff change.