Purpose: This study aimed to identify the effects of job stress, social support, and infection control fatigue on professional quality of life among nurses in designated coronavirus disease 2019 (COVID-19) hospitals. Methods: As a descriptive study, data were collected from 157 nurses working at four designated COVID-19 hospitals employing self-report questionnaires. The data were collected from September 1 to September 30, 2021, and analyzed using descriptive statistics, t-test, one-way ANOVA, Pearson’s correlation coefficients and stepwise multiple regression analysis. Results: Job stress, marital status and social support affected compassion satisfaction with the professional quality of life, showing 30% of explanatory power. Job stress and social support affected burnout with the professional quality of life, showing 34% of explanatory power. Infection control fatigue affected secondary traumatic stress in the professional quality of life and the explanatory power was 11%. Conclusion Efforts are needed to improve nurses' professional quality of life by preparing and applying interventions to reduce job stress and improve social support for nurses working in hospitals dedicated to COVID-19. Further, nursing efforts and institutional support will be needed to reduce infection control fatigue.