To systematically explore land use/cover change (LUCC) trends and driving mechanisms at the large watershed scale under the background of climate change and rapid urbanization. Taking the lower reaches of the Yangtze River (LRYR) as the research object, based on the land use remote sensing monitoring data from 1980 to 2020, the spatial and temporal evolution characteristics of LUCC in LRYR were analyzed by adopting the methods of land use dynamics degree (LUDD) and hotspot analysis and used geospatial detectors to quantitatively assess the intensity of the role of the land use change drivers in the LRYR. The results show that: 1) The land-use types in LRYR were dominated by arable land and woodland, accounting for more than 70% of the total area. During the study period, the construction land area increased by 11,835 km2, and became the third largest land-use type in LRYR after 2010 and formed a typical urban contiguous zone along the route from Nanjing to Shanghai. 2) The land use degree comprehensive index (LUDCI) in LRYR at each stage is 270.91, 270.88, 272.22, 272.72, 274.00, 275.57, 276.93 and 280.37, respectively. LUCC in LRYR has become more dramatic, and there is significant spatial heterogeneity. Shanghai has always been a hot area of LUCC and Huangshan and Chizhou are cold spots of LUCC. 3) The driving mechanism of LUCC in LRYR can be divided into three stages. In these three stages, secondary industry output value, precipitation, and elevation are always important factors affecting LUCC. The interaction between driving factors is significant. The strongest interaction is the output value of the secondary industry ∩ precipitation, the interaction reaches above 0.6. The research results are of great significance for promoting the sustainable development of land use in this region.