Abstract: Innovation has become an important driving force for regional economic development in the era of knowledge economy. This paper uses DEA-Malmquist index to measure regional innovation performance and spatial structure evolution of Yangtze Economic Zone, grouping regions with similar performance by Ward clustering method, analyzing innovation performance and problems. The results show that overall level of innovation performance in Yangtze Economic Zone is low, the development of core economic area mainly depends on R&D inputs and resource consumption, while the problem of how to improve utilization rate of existing technology is ignored. On one hand, regions at different development stages may have similar innovation performance, but experience different problems such as mismatch of resource scale and R&D input/output, input redundancy, lack of innovation output and so on. On the other hand, because the performance of regions at similar developmental stages are not the same, the specific ways to improve innovation performance are different. During 2000-2014, overall level of regional technology has improved significantly, while developing trend of regional production performance was gradually reduced. Technical level and performance show reverse trend of expansion, improvement of technology innovation mainly depends on input of resources, while how to improve the existing resources is worth further consideration. Specifically, 4 groups can be divided according to regional innovation performance. Overall level of innovation performance in cities at postindustrial stage is higher. Main problem of these cities is mismatch of resource scale and R&D input/output. Therefore, the most effective way for achieving optimal performance is adjusting resource scale. Less developed regions need optimize allocation of innovation resources by interregional cooperation. In addition, main problems for low innovation performance regions are lack of high-tech production output and application knowledge. Hence, main approach to improve innovation performance of these regions is continue expanding R&D resources and encouraging new product development.