The rapid development of urbanization in recent years has brought about economic and social development, but has led to a series of problems in the eco-environment. On the basis of the evaluation model of urbanization and eco-environment constructed for the Huaihe Eco-economic Belt, a comprehensive analysis of the coupling coordination degree between the two was conducted from 2005 to 2020, and the aggregation characteristics in space were explored, as well as the reasons for the uneven development of urbanization and eco-environment were revealed. The results show that: (1) between 2005 and 2020, the development level and the coupling coordination degree of urbanization and eco-environment in the Huaihe Eco-economic Belt all increased steadily. (2) In terms of global spatial autocorrelation, urbanization and coupling coordination showed a strong positive correlation in 2005, but weakened year by year as time progressed, while eco-environment shows a random spatial distribution. In terms of local autocorrelation, in 2005, urbanization local autocorrelation was mainly clustered in Shandong and Jiangsu Province, but both became more and more spatially dispersed as time progressed. (3) Spatial urbanization was the main aspect affecting the uneven level of urbanization in the Huaihe Eco-economic Belt in 2005, and by 2020, population urbanization had become a relatively weak aspect of urbanization in many cities, including Taizhou, Yancheng and Pingdingshan. In terms of eco-environment, between 2005 and 2015, ecological pressure became a problem for many cities, but in 2020, ecological pressure has weakened again, and soon the state of eco-environment has become a new weak point. The development of central cities such as Bengbu and Huai’an should be strengthened, talents should be retained, the urbanization rate of the population should be increased, and relevant environmental protection policies should be implemented to promote the sustainable development of cities within the Huaihe Eco-economic Belt.