Background: Nursing is a noble profession, which comes with a lot of responsibilities, workload, and demands made by the various stakeholders of health-care industry. Maintaining an empathic nurse–patient relationship is at its core, irrespective of the types of nursing care being rendered. This study aims to assess the association between perceived job stress and satisfaction, empathy, and spiritual beliefs on burnout and emotional distress, in nurses. Methodology: A cross-sectional research design was undertaken to meet the study objectives. Data were collected from a total of 257 consenting nurses, using the modified Consultants Job Stress and Satisfaction questionnaire, Maslach Burnout Inventory, Jefferson Scale of Physician Empathy-Health Provider Version, and General Health Questionnaire-12. Results: High empathy was related to lower depersonalization (DP) and higher personal accomplishment. Nurses who agreed on to their work beliefs being influenced by spiritual beliefs also had more commonly reported high job stress. More than a third (34.24%) of the nurses were emotionally distressed with a significant score in General Health Questionnaire-12 (GHQ-12). The GHQ-12 score significantly varied with high emotional exhaustion (EE), high DP, and job stress. Conclusion: Empathy and spiritual belief act as modifying factors for job stress and job satisfaction, respectively. A significant proportion of the nurses were found to have emotional distress which was significantly related to EE, DP, and job stress. A training module including strategies to build empathetic skills, stress management, and ways to promote psychological well-being, should be embedded in the curriculum of new graduate nurses. [ABSTRACT FROM AUTHOR]