Widespread human modification and conversion of land has led to loss and fragmentation of natural ecosystems, altering ecological processes and causing declines in biodiversity. The potential for ecosystems to adapt to climate change will be contingent on the ability of species to move and ecological processes to operate across broad landscapes. We developed a novel, robust modeling approach to estimate the connectivity of natural landscapes as a gradient of permeability. Our approach yields a map capable of prioritizing places that are important for maintaining and potentially restoring ecological flows across the United States and informing conservation initiatives at regional, national, or continental scales. We found that connectivity routes with very high centrality intersected proposed energy corridors in the western United States at roughly 500 locations and intersected 733 moderate to heavily used highways (104–106 vehicles per day). Roughly 15% of the most highly connected locations are currently secured by protected lands, whereas 28% of these occur on public lands that permit resource extraction, and the remaining 57% are unprotected. The landscape permeability map can inform land use planning and policy about places potentially important for climate change adaptation.