Molecular docking has been used for the high-throughput screening of chemical interactions with target proteins in pharmaceutical and environmental applications. We determined the in silico binding affinity, protein–chemical interactions, toxic potential, and hormone equivalents of 96 organic Unregulated Contaminant Monitoring Rule (UCMR 1–4) organic contaminants and agonist/antagonist standards with 10 nuclear receptors associated with environmental endocrine disruption. Endocrine-active pollutants and their toxic potentials were mapped across United States Public Water Systems (PWS). The percent of inactive UCMR chemicals varied greatly, from ∼38% for the thyroid system (TRα and TRβ) up to ∼70% for the estrogen system (ERα and ERβ), due to the presence of charged amino acid residues within the receptor’s ligand binding domains. Further, a majority of UCMR-detectable public water systems (4,900/5,229) contained thyroid-active chemicals, including perfluoroalkyl and polyfluoroalkyl substances (PFAS), haloacetic acids, and herbicide degradates. Most UCMR chemical classes were modeled with low toxic potential in monitored PWSs serving populations that varied between a few thousand and 100 million people. Insecticides, pesticides, herbicides, hormones, and PFAS had moderate toxic potential impacting a population of 10,000–20 million people. The potential for endocrine disruption by unregulated chemicals in public water systems calls for a further risk analysis of cumulative exposures.