This data release presents chemical results from investigations of surface-water quality in the Potomac River watershed (encompassing Washington, D.C. and parts of West Virginia, Virginia, Pennsylvania, and Maryland) conducted during low-flow conditions in July through September of 2022. This sampling campaign was conducted at 32 stream sites throughout the watershed (Table 1). A suite of field parameters and inorganic and organic chemical characteristics at each site were characterized using seven separate analytical methods at five laboratories (Table 2). The water-quality results are presented in Table 3. Analytical methods and laboratories used were (1) major anions by ion chromatography at the U.S. Geological Survey Integrated Water Chemistry Assessment Laboratory in Boulder, Colorado (USGSIWCAL); (2) excitation-emission-matrix (EEM) fluorescence spectroscopy dissolved organic carbon (DOC), and total dissolved nitrogen (TDN) at the U.S. Geological Survey California Water Science Center Organic Matter Research Laboratory in Sacramento, California (CAWSCOMRL); (3) per-and polyfluoroalkyl substances (PFAS) using liquid chromatography with tandem mass spectrometry (LC-MS/MS), at the U.S. Geological Survey National Water Quality Laboratory in Denver, Colorado (USGSNWQL); (4) pesticides (PEST) by LC-MS/MS or gas chromatography with tandem mass spectrometry (GS-MS/MS) at the U.S. Geological Survey Organic Research Laboratory (USGSOGCA); (5) pharmaceuticals (PHARM) using LC-MS/MS at the USGSNWQL; and (6) Major elements and trace elements (TEs) using inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma-optical emission spectrometry (ICP-OES) at the USGSIWCAL. Enzyme-Linked Immunosorbent Assay (ELISA) analyses were additionally performed at the U.S. Geological Survey Strategic Laboratory Science Branch in Boulder, Colorado (USGSSLSB) for the herbicides atrazine and glyphosate, the insecticide imidacloprid, and the consumer product chemical linear alkylbenzene sulfonate. Three analytes (atrazine, piperonyl butoxide, thiabendazole, and the thiabendazole surrogate standard thiabendazole-d4) were analyzed by the U.S. Geological Survey National Water Quality Laboratory (USGSNWQL) included with the pharmaceutical data in addition to being analyzed by the USGSOGCA with the pesticide data. The USGSNWQL results for these analytes were coded as replicate samples and additional time offsets were applied to create distinct times for these sample results. Samples were collected according to U.S. Geological Survey (USGS) protocols and procedures. A field blank and field replicate was collected for every analytical method, a matrix spike for PFAS, PHARM, and PEST was performed at three sites for quality assurance. Most sites were only sampled once for each parameter but four sites had to be resampled due to samples arriving too warm to be processed for PFAS and PHARM parameters. Therefore samples for the remaining parameters were collected twice at these four sites.