Wastewater-based epidemiology (WBE) is increasingly being recognized as a powerful tool for detecting and monitoring SARS-CoV-2 trends at a population level. This study looked to extend the use of WBE to explore the effectiveness of nonpharmaceutical interventions (NPIs) that have been used in response to COVID-19 and compare the results to the effect of such interventions on COVID-19 hospitalizations. A data-driven approach demonstrated that trends of SARS-CoV-2 RNA in wastewater, from Amsterdam and Utrecht (The Netherlands), precede hospitalizations by at least 3–9 days. Additionally, the effect of NPIs can be seen in wastewater and hospitalizations after 20 and 24 days, respectively. Changepoint analysis indicated that the closure of schools and universities significantly reduced the level of SARS-CoV-2 RNA in wastewater and COVID-19 hospitalizations. Regression modeling suggested the stay-at-home policy is an effective intervention for reducing the level of SARS-CoV-2 RNA in wastewater, whereas the closure of workplaces significantly reduced hospitalizations in both Dutch cities. This study demonstrates how WBE can be used to inform public health decisions and anticipate future strain on healthcare facilities in major cities but also indicates a need for higher temporal resolution of wastewater sampling.