With limited COVID-19-guidelines for institutions of higher education (IHEs), colleges and universities began the 2020–2021 academic year with varying approaches. We present a comprehensive COVID-19 prevention and mitigation approach at a residential university during the 2020–2021 academic year, along with campus SARS-CoV-2 transmission during this time. Risk management of COVID-19 was facilitated through (1) a layered approach of primary, secondary, and tertiary prevention measures; (2) a robust committee structure leveraging institutional public health expertise; (3) partnerships with external health entities; and (4) an operations system providing both structure and flexibility to adapt to changes in disease activity, scientific evidence, and public health guidelines. These efforts collectively allowed the university to mitigate SARS-CoV-2 transmission on campus and complete the academic year offering in-person learning on a residential campus. We identified 36 cases of COVID-19 among the 2037 in-person learners during the fall semester, 125 cases in the inter-semester break, and 169 cases among 2095 in-person learners during the spring semester. SARS-CoV-2 infection during the academic year was associated with gender (p = 0.04), race/ethnicity (p = 0.01), and sorority/fraternity membership (p < 0.01). Infection was not associated with undergraduate vs. graduate student status, Division I athlete status, or housing type (all p > 0.05). A multi-faceted public health approach was critical for reducing the impact of COVID-19 while carrying out the university’s educational mission.
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