Factors affecting groundwater quality used for domestic supply within the Marcellus Shale footprint in north-central and north-east Pennsylvania are identified using a combination of spatial, statistical, and geochemical modeling. Untreated groundwater, sampled during 2011–2017 from 472 domestic wells within the study area, exhibited wide ranges in pH (4.5–9.3), total dissolved solids (TDS, 22–1960 mg/L), sodium (0.3–760 mg/L), chloride (0.3–1020 mg/L), bromide (<0.01–8.6 mg/L), and methane (<0.001–77 mg/L). The wells had depths ranging from 10 to 394 m; 69.5 percent were completed in sandstone bedrock, 19.3 percent in shale, 4.2 percent in siltstone, 4 percent in carbonate, and 3 percent in unconsolidated alluvial or glacial deposits. Groundwater quality in the Delaware River watershed, in the eastern part of the study area where Marcellus gas has not been developed, was similar to that in the Susquehanna, Allegheny, and Genesee River watersheds in the western part of the study area where natural gas production from Marcellus Shale has been ongoing since 2008. Most groundwaters were calcium/bicarbonate type with near-neutral pH; approximately 10 percent were sodium/bicarbonate and 1 percent were sodium/chloride types. Sodium-enriched waters, which were mostly from shale and siltstone aquifers, had the greatest frequency of elevated pH (>8.5) and elevated concentrations of TDS (>250 mg/L), bromide (>0.15 mg/L), methane (>7.0 mg/L), and lithium (>60 μg/L). Geochemical models indicate these characteristics could result from progressive mineral dissolution combined with cation exchange, plus mixing with locally important salinity sources, including as much as 0.7 percent Appalachian Basin brine and/or road-deicing salt. Multivariate correlation models suggest the observed variability in methane concentrations may be attributed to several environmental factors, such as geochemical evolution along groundwater flow paths, redox conditions, and/or mixing with saline groundwater or brine. Most samples having elevated methane were from shale aquifers, which were mainly in the Susquehanna River basin and had the greatest density of gas wells compared to other lithologies. Samples having elevated methane were also observed in the Delaware River watershed and other areas outside gas development. Isotopic compositions of methane for a subset of 39 samples (selected because of elevated methane) and relatively high ratios of methane to ethane in those samples indicated methane could be derived from microbial gas mixed with thermogenic gas that may have undergone degradation and/or fractionation during migration. The methods used in this study could be broadly applicable to understanding major factors affecting groundwater quality, particularly for explaining variations in ionic composition with pH and identifying sources of salinity and associated constituents (e.g. sodium, chloride, bromide, lithium, methane) that may have geogenic or anthropogenic origins.