Land use/cover change (LUCC) is a measure that offers insights into the interaction between human activities and the natural environment, which significantly impacts the ecological environment of a region. Based on data from the period from 2000 to 2020 regarding land use, topography, climate, the economy, and population, this study investigates the spatial and temporal evolution of land use in the Liuchong River Basin, examining the interaction between human activities and the natural environment using the land use dynamics model, the transfer matrix model, the kernel density model, and the geodetic detector. The results indicate that: (1) The type of land cover in Liuchong River Basin primarily comprises cropland, forest, and shrubs, with the land use change mode mainly consisting of an increase in the impervious area and a decrease in surface area covered by shrubs. (2) The dynamic degree for single land use of barren, impervious, and waters indicates a significant increase, with areas covered by shrubs decreasing by 9.37%. In addition, the change in the degree of single land use for other types of cover is more stable, with the degree of comprehensive land use being 7.95%. The areas experiencing the greatest land use change in the watershed went through conditions that can be described as “sporadic distribution” to “dispersed” to “relatively concentrated”. (3) Air temperature, rainfall, and elevation are important factors driving land use changes in the Liuchong River Basin. The impact of nighttime lighting, gross domestic product (GDP), and normalized difference vegetation index (NDVI) on land use change have gradually increased over time. The results of the interaction detection indicated that the explanatory power of the interaction between the driving factors in each period for land-use changes was always greater than that of any single factor. The results of this study offer evidence-based support and scientific references for spatial planning, soil and water conservation, and ecological restoration in a watershed.