The Huaihe River Basin is one of the typical large river basin economies, promoting its ecological protection and high-quality development is a strategic choice to improve the quality of China's economic development and narrow the regional development gap, which has far-reaching strategic value for the region and the country in the new era. Based on the theoretical connotation of watershed ecological protection and high-quality economic development, starting from the special characteristics and practical features of the Huaihe River Eco-economic Belt, the panel data of 28 prefecture-level cities in the Huaihe River Eco-economic Belt from 2003–2018 are used as the research samples, the improved entropy method, Dagum Gini coefficient method and panel Tobit model investigate and analyze the time and space of ecological protection and high-quality development in the Huaihe Eco-economic Belt Evolution characteristics and promotion drivers. The results show that the overall ecological protection and high-quality development level of the Huaihe River Eco-economic Belt is 1.4824, showing an overall upward trend, with obvious periodic fluctuations; the high-value areas are mainly located in the lower and middle reaches of the basin, with the spatial agglomeration characteristic of “double core leading”, while the upper reaches are always in the stage of “low level and stable growth trap”; the hypervariable density is the main cause of the regional disparity; per capita output, opening to the outside world, human capital and government intervention drive the improvement of ecological protection and high-quality development. There are significant differences in the driving factors of ecological protection and high-quality development in the upper, middle and lower reaches of the city. The study of the development status of the Huaihe River Eco-economic Belt and its evolution law are of great theoretical significance, practical value for analyzing the synergistic enhancement path of urban ecological protection and high-quality development, promoting the ecological protection and high-quality economic development of the entire Huaihe River Basin.