This study identified clinical nurses’ fatigue and related factors during the COVID-19 pandemic. This was a cross-sectional study. Data were collected from South Korean hospitals on 234 nurses’ general characteristics, fatigue, depression, occupational stress, insomnia, and perceived daytime sleepiness using a structured questionnaire. The prevalence of fatigue was 62.0%, depression 52.1%, insomnia 20.7%, and daytime sleepiness 36.1%. Insomnia, sleepiness, depression, and occupational stress were significantly associated with fatigue. Ward nurses who cared for COVID-19 patients within the past month had significantly higher occupational stress related to organizational climate than those who had not provided care, and ICU nurses who cared for COVID-19 patients had significantly higher job insecurity-related occupational stress. Nurses have a high prevalence of fatigue and depression during the pandemic. Thus, insomnia, sleepiness, depression, and occupational stress must be reduced to lower nurses’ fatigue. Caring for COVID-19 patients was not significantly associated with fatigue, but there were significant differences in occupational stress between nurses who provided such care and those who did not. Work environment-specific strategies are needed to reduce nurses’ occupational stress during the pandemic.