Concerns over unconventional oil and gas (UOG) development persist, especially in rural communities that rely on shallow groundwater for drinking and other domestic purposes. Given the continued expansion of the industry, regional (vs local scale) models are needed to characterize groundwater contamination risks faced by the increasing proportion of the population residing in areas that accommodate UOG extraction. In this paper, we evaluate groundwater vulnerability to contamination from surface spills and shallow subsurface leakage of UOG wells within a 104,000 km2 region in the Appalachian Basin, northeastern USA. We test a computationally efficient ensemble approach for simulating groundwater flow and contaminant transport processes to quantify vulnerability with high resolution. We also examine metamodels, or machine learning models trained to emulate physically based models, and investigate their spatial transferability. We identify predictors describing proximity to UOG, hydrology, and topography that are important for metamodels to make accurate vulnerability predictions outside their training regions. Using our approach, we estimate that 21,000-30,000 individuals in our study area are dependent on domestic water wells that are vulnerable to contamination from UOG activities. Our novel modeling framework could be used to guide groundwater monitoring, provide information for public health studies, and assess environmental justice issues.