The Development of the Yangtze River Economic Belt (YREB) is not only a major regional coordination development strategy in China but also a core carrier supporting China’s innovation-driven development. Under this background, this paper explored the evolution, spatial difference, and coordination development of the regional innovation system in the period of 2007 to 2017 from the demand and supply perspective. We found that, during the study period, the development level of the innovation demand subsystem (IDS) and innovation supply subsystem (ISS), as well as their coordinated development, all showed an increasing trend. The development gap of IDS and the coordinated development among cities in YREB was quite balanced, while there existed a large gap among cities in YREB in the development of ISS. The development of IDS was better than the development of ISS in most of the cities of YREB, indicating that the innovation development of cities in YREB needs supply-side structural reform urgently. Most cities in YREB were at the moderately or slightly uncoordinated development phase, and Shanghai was the only city with coordinated development between IDS and ISS. This paper enriches the regional innovation system from a new perspective, the demand and supply perspective, as well as providing suggestions for the coordinated development of the regional innovation system in YREB.