Purpose: This study aimed to gain an in-depth understanding by analyzing and exploring the work experience of infection control nurses (ICNs) in response to the prolonged COVID-19 pandemic. Methods: Data were collected from 14 ICNs, (two in in-depth interviews and 12 in groups of six) from February 19, 2021, to March 20, 2021, and were analyzed according to the content. Results: In the prolonged COVID-19 pandemic, ICNs took the lead in responding to infectious diseases, where they felt pressure in doing everything. In addition, they were confused by a lack of workforce and undetailed job plans. ICNs have been exhausted by insufficient support and system, such as the lack of support in the hospital, communication with health authorities, and difficulties with patients and visitors. However, ICNs settle with the help and encouragement of those around them. For example, pride in the work that only ICN can do, change in the cooperation of hospitals, and development of ICNs’ unique method of perseverance. Conclusion: During the COVID-19 pandemic, ICNs experienced structural, physical, and mental difficulties at work. Nevertheless, the study found that a driving force enabled ICNs to endure, and that to efficiently respond to new infectious diseases in the future, it is necessary to secure ICNs and strengthen them.