The Huai River is an important flood control and discharge river in the middle and east of China, and the development of ecological economy with regional advantages is significant for the protection and improvement of the resources and environment of the basin. On the basis of defining the connotation of an ecological economic system, this study constructed an index system, and it applied the methods of data envelopment analysis (DEA) and exploratory spatial data analysis (ESDA) to study the ecological economy of the Huai River. This study concluded that (1) the efficiency in most areas was efficient, but inefficient in a few areas; (2) the causes of inefficiency were unreasonable production scale and unqualified production technology, which led to redundant input of resources, insufficient output of days with good air quality, and excessive output of particulate matter with less than or equal to 2.5 microns in diameter (PM2.5); and (3) the efficiency was different in different regions, so it was necessary to respectively formulate and implement strategies for protection and development of resources and environment. The research results can be used as an important reference for formulating ecological economic policies around the world.