A pilot-scale expanded target assessment of mixtures of inorganic and organic contaminants in point-of-consumption drinking water (tapwater, TW) was conducted in Puerto Rico (PR) to continue to inform TW exposures and corresponding estimations of cumulative human-health risks across the US. In August 2018, a spatial synoptic pilot assessment of than 524 organic, 37 inorganic, and select microbiological contaminant indicators was conducted in 14 locations (7 home; 7 commercial) across PR. A follow-up 3-day temporal assessment of TW variability was conducted in December 2018 at two of the synoptic locations (1 home, 1 commercial) and included daily pre- and post-flush samples. Concentrations of regulated and unregulated TW contaminants were used to calculate cumulative in vitro bioactivity ratios and Hazard Indices (HI) based on existing human-health benchmarks. Synoptic results confirmed that human exposures to inorganic and organic contaminant mixtures, which are rarely monitored together in drinking water at the point of consumption, occurred across PR and consisted of elevated concentrations of inorganic contaminants (e.g., lead, copper), disinfection byproducts (DBP), and to a lesser extent per/polyfluoroalkyl substances (PFAS) and phthalates. Exceedances of human-health benchmarks in every synoptic TW sample support further investigation of the potential cumulative risk to vulnerable populations in PR and emphasize the importance of continued broad characterization of drinking-water exposures at the tap with analytical capabilities that better represent the complexity of both inorganic and organic contaminant mixtures known to occur in ambient source waters. Such health-based monitoring data are essential to support public engagement in source water sustainability and treatment and to inform consumer point-of-use treatment decision making in PR and throughout the US.