Climate change, income and population growth, and changing diets are major stressors for global agricultural markets with implications for land use change. US land use 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 advanced the capabilities in representing the interactions between natural and human system through a collaborative effort between two MSD teams. This effort couples 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. We exemplify the framework over the Mississippi river basin and consider the effects of a range of global drivers and stressors, such as: high or low economic and population growth, more negative or more positive impacts of climate change, and more or less dietary change. The resulting regional land use changes are further translated into more detailed projections of land use changes through the downscaling model. In addition, we examine assumptions, including 1) how global stressors might, in combination, affect regional land use change and 2) how alternative rules and constraints spatialize the regional projections. Our results help better understand the implications of land use change on carbon storage, soil erosion, chemical use, hydrology, and water quality. The employed downscaling model facilitates interoperability among models and across various spatial scales. The presented framework can be readily applied to other basins with little effort.