The rapid development of urbanization in recent years has led to significant economic and social progress, but it has also resulted in a series of eco-environmental challenges. This study, based on an evaluation model of urbanization and eco-environment for the Huaihe Ecological Economic Belt, conducts a comprehensive analysis of the coupling coordination degree between the two from 2005 to 2020, explores spatial aggregation characteristics, and reveals the reasons for the uneven development of urbanization and the eco-environment. The results are as follows: (1) Between 2005 and 2020, both the development level of urbanization and the coupling coordination degree between urbanization and the eco-environment steadily increased. (2) Global spatial autocorrelation analysis shows that in 2005, urbanization and coupling coordination exhibited a strong positive correlation, which weakened over time, while the eco-environment displayed a random spatial distribution. Local autocorrelation analysis reveals that in 2005, urbanization showed significant spatial clustering in Shandong and Jiangsu provinces, but this clustering became more spatially dispersed over time. (3) In 2005, spatial urbanization was the main factor contributing to the uneven level of urbanization in the Huaihe Ecological Economic Belt. By 2020, population urbanization had become a relatively weak factor in cities such as Taizhou, Yancheng, and Pingdingshan. Regarding the eco-environment, ecological pressure was a prominent issue between 2005 and 2015, but by 2020, ecological pressure had weakened, and the eco-environmental state became a new area of concern. To promote sustainable development in the Huaihe Ecological Economic Belt, it is essential to strengthen the development of central cities such as Bengbu and Huai'an, retain talent, increase the urbanization rate, and implement effective environmental protection policies. These measures will contribute to the region's long-term ecological and urban sustainability.