The invasion of wetlands by Phragmites australis is a conservation concern across North America. We used the invasion of Chesapeake Bay wetlands by P. australis as a model system to examine the effects of regional and local stressors on plant invasions. We summarized digital maps of the distributions of P. australis and of potential stressors (especially human land use and shoreline armoring) at two spatial scales: for 72 subestuaries of the bay and their local watersheds and for thousands of 500 m shoreline segments. We developed statistical models that use the stressor variables to predict P. australis prevalence (% of shoreline occupied) in subestuaries and its presence or absence in 500 m segments of shoreline. The prevalence of agriculture was the strongest and most consistent predictor of P. australis presence and abundance in Chesapeake Bay, because P. australis can exploit the resulting elevated nutrient levels to enhance its establishment, growth, and seed production. Phragmites australis was also positively associated with riprapped shoreline, probably because it creates disturbances that provide colonization opportunities. The P. australis invasion was less severe in areas with greater forested land cover and natural shorelines. Surprisingly, invasion was low in highly developed watersheds and highest along shorelines with intermediate levels of residential land use, possibly indicating that highly disturbed systems are uninhabitable even to invasive species. Management strategies that reduce nutrient pollution, preserve natural shorelines, and limit nearshore disturbance of soils and vegetation may enhance the resilience of shorelines to invasion.