Climate change, income and population growth, and changing diets are major stressors for global agricultural markets with implications for land use change. Land use in the United States at regional and local scales is directly affected by domestic forces and indirectly through international trade. In order to investigate the effects of several potential forces on land use changes in the US at multiple spatial scales, we advance capabilities in representing the interactions between natural and human system through a collaborative effort between two MSD teams. This effort links a multi-sectoral and multi-regional socio-economic model of the world economy with detailed representation of land use and agricultural systems to an open-source downscaling model which enables translating regional projections of future land use into high-resolution representations of time-evolving land cover. This enables us to translate regional projections of future land use (represented as net land use) into higher-resolution (0.5°grid scale) representations of time-evolving land cover (effectively spatially explicit gross land use). We apply the framework over the U.S., with a particular interest in four sub-basins of the Mississippi River, to consider how a range of global drivers and stressors affect land use and cover in the target regions. Driving forces and stressors include high or low economic and population growth, more negative or more positive impacts of climate change, and more or less dietary change. Our results show that a comparative advantage in livestock production leads to shifts from cropland to pastures in the U.S. under scenarios of high pressure on the world food system. However, there can be key differences across the various land-use transitions at the sub- basin scale, driven not only by regional economic pressures but also the evolving patterns of land use. Overall, these results highlight the need for high resolution details to explicitly understand the implications of land use change on environmental impacts such as carbon storage, soil erosion, chemical use, hydrology, and water quality.