This article constructs a comprehensive evaluation index system from four aspects: economic vitality, innovation efficiency, green development, and people’s lives. Use the entropy method to comprehensively measure the urban competitiveness level of 25 counties and cities in the economic zone, clarify the differences in their high-quality development levels, and use spatial econometric analysis methods to study the spatial agglomeration and dispersion and spatial convergence of regional urban competitiveness. The results show that the following: (1) the overall high-quality development level of the Huaihe River Eco-Economic Zone is not high, and the overall time and space characteristics is “high in the east and low in the west”; (2) there is a positive spatial autonomy in urban competitiveness and the spatial distribution of the Huaihe River, and relevantly, the degree of closeness of spatial associations between cities is generally low; (3) the gap between the level of urban competitiveness in Jiangsu Province is shrinking, the development of other provinces has a time lag effect, and there are differences in the level of urban competitiveness. Finally, to promote the high-quality development of the Huaihe Economic Zone, we must follow the law of the basin and the characteristics of spatial distribution and implement targeted strategies.