The middle reaches of the Yangtze River region (MRYRR) are China’s first trans-regional urban agglomeration, located in the center of the Yangtze River Economic Belt. The MRYRR is an important ecological reserve, and its land cover changes are affected by both socio-economic development and geographical environment. In this paper, Landsat ETM/TM/OLI remote sensing images were used to monitor land use and landscape patterns from 1990 to 2015. Through supervised classification, land use transfer matrix, landscape pattern metrics and correlation analysis, the spatial-temporal patterns of land use change and its relationship with socio-economic in the study area were revealed. The results showed that: (1) the main land use types in the study area were cropland (CL) and forestland (FL), accounting for more than three-quarters of the study area. During the study period, built-up land (BL) increased, CL decreased, FL increased first and then decreased; (2) the BL expanded mainly by occupying CL and FL, and regional landscape pattern was gradually fragmented, with complex patch shape and increasing diversity and heterogeneity. Among them, the BL is gradually gathered, and the FL and CL are gradually fragmented; (3) in the past 25 years, the urbanization process in this region has been obvious, and the Gross Domestic Product (GDP) has increased by 36 times. The socioeconomic variables were positively correlated with BL, orchard (OL) and Shannon diversity index (SHID), and negatively correlated with CL, Wasteland (WL), mean patch size (MPS) and contagion size (CONTAG). The results showed that the urbanization development has a great impact on the region, and the ecological protection task is still challenging. It is necessary to protect high-quality cropland and draw a red line for ecological protection. We should strengthen the construction of ecological corridors and ecological nodes to adapt to regional sustainable development.