A recent paradigm shift from purely biophysical towards social-ecological assessment of watersheds has been proposed to understand, monitor, and manipulate the myriad interactions between human well-being and the ecosystem services that watersheds provide. However, large-scale, quantitative studies in this endeavour remain limited. We utilised two newly developed ‘big-data’ sets—the Index of Watershed Integrity (IWI) and the Human Well-Being Index (HWBI)—to explore the social-ecological condition of watersheds throughout the conterminous U.S., and identified environmental and socio-economic influences on watershed integrity and human well-being. Mean county IWI was highly associated with ecoregion, industry-dependence, and state, in a spatially-explicit regression model (R2 = 0.77, P < 0.001), whereas HWBI was not (R2 = 0.31, P < 0.001). HWBI is likely influenced by factors not explored here, such as governance structure and formal and informal organisations and institutions. ‘Win-win’ situations in which both IWI and HWBI were above the 75th percentile were observed in much of Utah, Colorado, and New Hampshire, and lessons from governance that has resulted in desirable outcomes might be learnt from here. Eastern Kentucky and West Virginia, along with large parts of the desert southwest, had intact watersheds but low HWBI, representing areas worthy of further investigation of how ecosystem services might be utilised to improve well-being. The Temperate Prairies and Central USA Plains had widespread areas of low IWI but high HWBI, likely a result of historic exploitation of watershed resources to improve well-being, particularly in farming-dependent counties. The lower Mississippi Valley had low IWI and HWBI, which is likely related to historical (temporal) and upstream (spatial) impacts on both watershed integrity and well-being. The results emphasise the importance of considering spatial and temporal trade-offs when utilising the ecosystem services provided by watersheds to improve human well-being.