Wastewater-based epidemiology (WBE) is used to determine the consumption of, or exposure to, chemicals or pathogens in human populations, and is conducted by collecting representative samples of untreated wastewater (influent) to quantify pathogens shed in the population served by the sampled wastewater system. The Centers for Disease Control and Prevention (CDC) and the US Department of Health and Human Services (HHS), in collaboration with the United States Geological Survey (USGS) and other agencies throughout the federal government, initiated the National Wastewater Surveillance System (NWSS) in response to the COVID-19 pandemic to conduct WBE using analytical methods for the collection and analysis of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in wastewater influent. The data generated by NWSS helps public health officials to better understand the extent of SARS-CoV-2 infections in communities. Surge capacity sampling to support NWSS and carried out by the USGS was conducted in September 2021 in six states (Colorado, Missouri, Utah, North Carolina, Ohio, and Wisconsin). 354 samples from 25 wastewater treatment plants (WWTP) representing 26 distinct service areas (one facility has two treatment areas) were analyzed using ddPCR (digital droplet polymerase chain reaction) for SARS-CoV-2 using standard CDC assays targeting N2- and E-genes plus the wastewater marker pepper mild mottle virus (PMMoV). Results for both genes are included in this data release (708 records).