Groundwater is a vital resource in the Mississippi embayment of the central United States. An innovative approach using machine learning (ML) was employed to predict groundwater salinity—including specific conductance (SC), total dissolved solids (TDS), and chloride (Cl) concentrations—across three drinking-water aquifers of the Mississippi embayment. A ML approach was used because it accommodates a large and diverse set of explanatory variables, does not assume monotonic relations between predictors and response data, and results can be extrapolated to areas of the aquifer not sampled. These aspects of ML allowed potential drivers and sources of high salinity water that have been hypothesized in other studies to be included as explanatory variables. The ML approach integrated output from a groundwater-flow model and water-quality data to predict salinity, and the approach can be applied to other aquifers to provide context for the long-term availability of groundwater resources. The Mississippi embayment includes two principal regional aquifer systems; the surficial aquifer system, dominated by the Quaternary Mississippi River Valley Alluvial aquifer (MRVA), and the Mississippi embayment aquifer system, which includes deeper Tertiary aquifers and confining units. Based on the distribution of groundwater use for drinking water, the modeling focused on the MRVA, middle Claiborne aquifer (MCAQ), and lower Claiborne aquifer (LCAQ). Boosted regression tree (BRT) models (Elith and others, 2008; Kuhn and Johnson, 2013) were developed to predict SC and Cl to 1-kilometer (km) raster grid cells of the National Hydrologic Grid (Clark and others, 2018) for 7 aquifer layers (1 MRVA, 4 MCAQ, 2 LCAQ) following the hydrogeologic framework of Hart and others (2008). TDS maps were created using the correlation between SC and TDS. Explanatory variables for the BRT models included attributes associated with well location and construction, surficial variables (such as soils and land use), and variables extracted from a MODFLOW groundwater flow model for the Mississippi embayment (Haugh and others, 2020a; Haugh and others, 2020b). Prediction intervals were calculated for SC and Cl by bootstrapping raster-cell predictions following methods from Ransom and others (2017). For a full description of modeling workflow and final model selection see Knierim and others (2020).