Improving eco-efficiency is an important way to mitigate the resource and environmental constraints during the process of economic growth. This paper uses SE-SBM model to study the eco-efficiency in the Yangtze River economic zone for the period of 2005 to 2015. Meanwhile, this paper studies the key influencing factors of eco-efficiency with the use of Spatial Lag Model. And the results show that in the sample period, the eco-efficiency in the Yangtze River economic zone are all in an ineffective state, and improvement is possible and necessary. The eco-efficiency in Yangtze River economic zone is distributed in wave shape in time series. The eco-efficiency of the lower reaches presents an increasing trend; while the eco-efficiency of the upper and middle reaches are quite the opposite. The results of the spatial correlation test show that the global spatial cluster degree of Yangtze River is continually growing. The high-high cluster areas concentrate in three provinces at lower reaches, which are Zhejiang, Jiangsu and Shanghai. The high-low cluster area is located in Chongqing. And the low-low cluster areas and low-high cluster areas concentrate in upper and middle reaches of Yangtze River. The results show that methods of improving the urbanization level, optimizing the industrial structure, promoting technological progress, strengthening the intensity of environmental regulation, together with the richness in natural resources can promote eco-efficiency, while the improving the proportion of state-owned economy in economic entity is not conducive to improving eco-efficiency of Yangtze River.