Wastewater-based surveillance (WBS) has been established as a powerful tool that can guide health policy at multiple levels of government. However, this technology has not been well assessed at more granular scales, including large work sites such as University campuses. Between August 2021-April 2022, we explored the occurrence of SARS-CoV-2 RNA in wastewater from multiple complimentary sewer catchments and residential buildings spanning the University of Calgary’s campus and how this compared to levels from the municipal wastewater treatment plant servicing the campus. Concentrations of wastewater SARS-CoV-2 N1 and N2 RNA varied significantly across six sampling sites – regardless of several normalization strategies – with certain catchments consistently demonstrating values 1–2 orders higher than the others. Additionally, our comprehensive monitoring strategy enabled an estimation of the total burden of SARS-CoV-2 for the campus per capita, which was significantly lower than the surrounding community (p≤0.01). Real-time contact tracing data was used to confirm an association between wastewater SARS-CoV-2 burden and clinically confirmed cases proving the potential of WBS as a tool for disease monitoring across worksites. Allele-specific qPCR assays confirmed that variants across campus were representative of the community at large, and at no time did emerging variants first debut on campus. This study demonstrates how WBS can be efficiently applied to locate hotspots of disease activity at a very granular scale, and predict disease burden across large, complex worksites.Synopsis‘This study establishes that wastewater-based surveillance with a node-based sampling strategy can be used to passively monitor for disease, locate disease “hotspots” and approximate the burden of infected individuals’