Background The COVID-19 pandemic has affected infection prevention and control (IPC) programs worldwide. We evaluated the impact of COVID-19 on the University of Iowa Hospitals & Clinics IPC program by measuring the volume of calls to the program, changes in healthcare-associated infection rates, and team member perceptions. Methods We retrieved the IPC call log and healthcare-associated infection trends for 2018-2020. We defined 2 periods: pre-COVID-19 (2018-2019) and COVID-19 (January-December 2020). We also conducted one-on-one interviews and focus group interviews with members of the IPC program and describe changes in their working conditions during the COVID-19 period. Results A total of 6,564 calls were recorded during 2018-2020. The pre-COVID-19 period had a median of 71 calls and/or month (range: 50-119). During the COVID-19 period, the median call volume increased to 368/month (range: 149-829), and most calls were related to isolation precautions (50%). During the COVID-19 period, the central line-associated bloodstream infection incidence increased significantly. Infection preventionists reported that the ambiguity and conflicting guidance during the pandemic were major challenges. Conclusions Our IPC program experienced a 500% increase in consultation requests. Planning for future bio-emergencies should include creative strategies to increase response capacity within IPC programs.