Background The COVID-19 pandemic has risen to the top of the public's concentration. Epidemics generate societal stigma. Contagion stimulates numerous preconceptions, views, emotional states, labels, stereotypes, and stigmas. Emotions play a crucial role in these situations, affecting planned or fact-based decisions. Today amid COVID-19, nurses in a challenge for caring for patients. There is a conflict between the professional obligation due by nurses to their patients and the contagion-induced tacit attitudes. A fear begins during outbreaks as a result of concern about an unidentified reason disease with a potentially lethal end, particularly when infection control procedures such as quarantine and strict isolation are executed to safeguard the public. Aim: This study aimed to explore the relationship between COVID-19 stigma and nurses’ professional quality of life, self-esteem, and performance. The objectives were to assess the level of COVID-19 stigma, nurses' professional quality of life, self-esteem, and performance, and examine correlations among all variables. Research design: The exploratory correlational design was used to achieve the objectives of the present study Settings: This study was conducted at Zagazig University Hospitals (ZUH’s), Zagazig University, in Asharqia, Egypt Subjects: A stratified proportionate random sample (n=326) from different categories of nurses, and a Jury committee (n=7). Study tools: 4 Questionnaires format and 4 opinionnaire sheets were utilized for data collection. Results: 56.1% of study subjects have a high level of social stigma. there were statistically significant differences between COVID-19 social stigma and nurses’ performance (task dimension at p-value 0.004, Contextual dimension at p-value 0.0001 and Counterproductive dimension at p-value 0.0001, nurses’ self-esteem at p-value 0.001, and nurses' professional quality of life (satisfaction at p-value 0.002, nurses' burnout at p -value 0.0001, and nurses' fatigue at p -value 0.0001). Conclusion and Recommendations: nurses have a high level of stigma. COVID-19 stigma was associated with nurses’ performance, self-esteem, and professional quality of life. Nurses’ self-esteem and professional quality of life were associated with nurses’ performance. Stigma predicts performance (contextual dimension), Self-esteem predicts performance (task and counterproductive dimension), satisfaction predicts performance dimensions, burnout predicts task, contextual dimensions, and stigma, and finally, fatigue predicts counterproductive dimension. Thus, strategies and measures should be taken, to promote nurses’ quality of life, self-esteem, and performance; keep nurses away from fatigue, burnout, and stigmas; enforce positive public attitudes toward nurses; continuing education and training sessions; and support.