The COVID-19 pandemic forced most institutions of higher education to offer instruction and activities offsite, impacting millions of people. As universities consider resuming normal operations on campus, evidence-based guidance is needed to enhance safety protocols to reduce the spread of infectious disease in their campus environments. During the 2020/2021 academic year, Gannon University in Erie, PA, USA, was able to maintain most of its operations on campus. Part of Gannon’s disease mitigation strategy involved the development of a novel in-house, real-time RT-PCR-based surveillance program, which tested 23,227 samples to monitor the presence of COVID-19 on campus. Temporal trends of COVID-19 infection at Gannon were distinct from statewide data. A significant portion of this variance involved student athletes and associated staff, which identified as a higher incidence risk group compared with non-athletes. Rapid identification of athlete driven outbreaks allowed for swift action to limit the spread of COVID-19 among teammates and to the rest of the campus community. This allowed for successful completion of instruction and a modified season for all sports at Gannon. Our findings provide insights that could prove useful to the thousands of institutions seeking to resume a more traditional presence on campus.