Future climate and land-use changes and growing human populations may reduce the abundance of water resources relative to anthropogenic and ecological needs in the Northeast and Midwest (U.S.). We used output from WaSSI, a water accounting model, to assess potential changes between 2010 and 2060 in (1) anthropogenic water stress for watersheds throughout the Northeast and Midwest and (2) native fish species richness (i.e., number of species) for the Upper Mississippi water resource region (UMWRR). Six alternative scenarios of climate change, land-use change, and human population growth indicated future water supplies will, on average across the region, be adequate to meet anthropogenic demands. Nevertheless, the number of individual watersheds experiencing severe stress (demand > supplies) was projected to increase for most scenarios, and some watersheds were projected to experience severe stress under multiple scenarios. Similarly, we projected declines in fish species richness for UMWRR watersheds and found the number of watersheds with projected declines and the average magnitude of declines varied across scenarios. All watersheds in the UMWRR were projected to experience declines in richness for at least two future scenarios. Many watersheds projected to experience declines in fish species richness were not projected to experience severe anthropogenic water stress, emphasizing the need for multidimensional impact assessments of changing water resources.