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We sought to create and implement a set of COVID-19 mitigation processes including reliable testing to minimize in-school transmission of SARS-CoV-2. A large urban school district (> 33,000 students), a city health department, and a free-standing children’s hospital partnered to implement multi-layered mitigation procedures which included access to polymerase chain reaction (PCR) testing with same day or next morning results. We tracked COVID-19 cases as well as probable/confirmed transmissions and identified needed mitigations through frequent huddles. During the 2020–2021 school year, there were 13 weeks of hybrid in person learning and 9 weeks of 5 day a week learning. Of the 1936 cases documented, only 3.2% resulted in subsequent school-related transmission. When children felt ill in the classroom, they were isolated within 10 min of reporting ill symptoms (> 90% of the time). PCR test results were routinely available to the school district by 6AM the following morning (79–99% of the time, depending on the learning model). An adaptive, fast-learning partnership across school district, public health, and a children’s hospital minimized school-related transmission of COVID-19 and allowed children to safely return to the classroom. Supplementary Information The online version contains supplementary material available at 10.1007/s10900-022-01067-7.

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