Understanding the complex interactions between climate change, urbanization, land use and land cover change (LULCC), and drought is essential for addressing future water stress challenges. Previous studies examining these interactions have not fully accounted for the impact of urban expansion or considered various types of bioenergy crops for achieving climate mitigation goals. Here, we use an integrated multisector, multiscale modeling framework designed to explore how climate change, urban expansion, land-based climate mitigation strategies (e.g., bioenergy) may influence hydrological feedbacks, specifically alleviating or compounding water stress across the Continental United States (CONUS). Our framework integrates the Weather Research and Forecasting (WRF) model, the Global Change Analysis Model (GCAM-USA), and the Community Land Model (CLM), along with Demeter to harmonize models and data from different scales to a consistent 1/8° spatial resolution. We employ this WRF-GCAM-CLM framework for scenario-driven, long-term simulations of the terrestrial hydrological system over the CONUS. Eight future scenarios are represented, featuring four climate projections based on two scenarios each for RCP4.5 and RCP8.5 that reflect “hotter” versus “cooler” CMIP6 models, combined with SSP3 and SSP5 socioeconomic assumptions. These scenarios provide the exogenous drivers needed for our CONUS-scale modeling of climate-energy-water-land interactions. Distinct from prior research, our framework uniquely incorporates 1) dynamic urban expansion projections from the Spatially-Explicit, Long-term, Empirical City developmenT (SELECT) model, harmonized with non-urban LULCC from GCAM-USA; 2) a spectrum of bioenergy crop expansions including rainfed woody biomass crops; and 3) optimized regional hydrological parameters identified through CLM uncertainty characterization, enhancing the large-domain hydrological modeling. This comprehensive framework will be used to assess the regional vulnerabilities to hydrological droughts and elucidate the driving mechanisms behind them, providing crucial insights to inform effective regional strategies for managing terrestrial water resources.