Exploring the relationship between land use change and landscape patterns can provide a basis for regional ecological management. In this paper, based on remote sensing images of the Huaihe River Ecological and Economic Zone for the years 2000, 2005, 2010, 2015 and 2020, the spatial and temporal evolution patterns of land use in the region were quantitatively described by using the methods of land use shift matrix and landscape pattern analysis. The relationship between land use change and landscape pattern was analyzed with the Grey Relation Analysis (GRA) model. The results show that: (1) the land use of the Huaihe River Ecological and Economic Zone has changed significantly in the past 20 years, with the conversion of arable land into construction and forest lands, in addition to the growth of water areas and a decline in the areas of arable land, grassland and unused land. (2) The landscape pattern fragmentation of each type of land in the study area from 2000 to 2020 fluctuated and decreased, and the landscape connectivity and landscape diversity increased significantly. (3) The GRA model shows that construction, arable and forest lands played the most significant role in the change of landscape pattern of the Huaihe River Ecological and Economic Zone. Countermeasures are proposed to better coordinate and optimize the relationship between spatial development and landscape pattern for the Huaihe River ecological and economic Zone.