The aim of the study was to analyze the role of global self-esteem and professional burnout in predicting Polish nurses' quality of life. Materials and Methods: The research involved 1806 nurses who were employed in 23 hospitals in north-eastern Poland. Forty-seven percent of nurses, aged ≤44 years, were qualified to Group 1, while 53% of nurses, aged ≥45 years, were included in Group 2. A diagnostic survey was applied as a research method. For the collection of data, the WHOQoL-Bref questionnaire, the Rosenberg Self-Esteem Scale and the Copenhagen Professional Burnout Inventory were used. For the statistical analysis, the significance level of P < 0.05 was adopted. Results: Global self-esteem had a positive orientation towards the prediction of the quality of life among the younger nurse group in the psychological and social domains by explaining 20% (ßeta = 0.33; R 2 = 0.20) and 15% (ßeta = 0.28; R 2 = 0.15) of the result variation, respectively. In the older nurse group, personal burnout, which took a negative orientation in the somatic (ßeta = −0.33 R 2 = 0.19), social (ßeta = −0.37; R 2 = 0.17) and environmental domains (ßeta = −0.28; R 2 = 0.32), had the greatest share in predicting the quality of life. Conclusion: There is a need for the implementation of professional burnout prevention programs, as professional burnout adversely affects the quality of life in the somatic, social and environmental domain, particularly in the older nurse group.