Groundwater samples collected during 2012 and 2013 from public-supply wells screened in the Atlantic and Gulf Coastal Plain aquifers of the eastern and southeastern U.S. rarely contained lead or manganese concentrations that exceeded drinking-water limits, despite having corrosive characteristics. Data indicate that the occurrence of dissolved lead and manganese in sampled groundwater, prior to its distribution or treatment, was related to several explanatory factors including the presence of source minerals, hydrologic position along the flow path, water-rock interactions, and associated geochemical conditions such as pH and dissolved oxygen (DO) concentrations. Elevated concentrations of lead compared to health-based benchmarks were associated with groundwater that is acidic (pH ≤ 6.5), oxygenated (DO ≥ 2 mg/L), and closer to recharge zones (relatively young water). Elevated concentrations of manganese were associated with groundwater that is acidic to neutral (pH ≤ 7.5), has low DO (<2 mg/L), and further from recharge zones (relatively old). Under these geochemical conditions, minerals that could sequester lead or manganese tended to be undersaturated, and adsorption by hydrous ferric oxide was limited. Under neutral to alkaline pH conditions, precipitation of impure calcium carbonate or phosphate compounds containing traces of lead or manganese (solid solutions) could maintain low concentrations of the trace elements. Additionally, adsorption of lead or manganese cations by hydrous ferric oxides (HFO) could be another attenuating factor where conditions are oxidizing and dissolved inorganic carbon concentrations are relatively low. A DO/pH framework was developed as a screening tool for evaluating risk of elevated lead or manganese, based on the occurrence of elevated lead and manganese concentrations and the corresponding distributions of DO and pH in the Atlantic and Gulf Coastal Plain aquifers. Validation of the DO/pH framework was accomplished using an independent national dataset that showed consistent results for elevated lead (pH ≤ 6.5; DO ≥ 2 mg/L) and manganese (pH ≤ 7.5; DO < 2 mg/L).