Introduction: Nursing can be highly rewarding, but at the same time, overwhelmingly stressful or even traumatizing. Spirituality constitutes a central element of nurses’ resilience, while personal trauma may be activated during exposure to patients’ trauma. Aim: The aim of this study was to examine the impact of sociodemographic and work-related characteristics, spirituality, and personal trauma history on compassion fatigue and compassion satisfaction among Greek nurses. Methods: A cross-sectional survey study with a total of 210 nurses selected by convenience sampling and required to complete the Professional Quality of Life Scale (ProQOL V), the FACIT-Spiritual Well-Being Scale-12 nonillness scale, and the Traumatic Life Events Questionnaire (TLEQ). Results: Thirty percent (30%) of the participants reported high compassion fatigue risk, while 76% expressed high to moderate potential for compassion satisfaction. Secondary traumatic stress (STS), as expected, was found to correlate positively with traumatic life events. Compassion satisfaction scores were found to correlate positively with spiritual well-being and the three aspects of meaning, peace, and faith. Nurses who reported good physical health, high levels of cooperation, respect for teamwork, and positive work climate also reported higher levels of Compassion Satisfaction and lower risk for compassion fatigue. Conclusion: The findings of this study shed light on the significant prevalence of compassion fatigue among nursing staff, highlighting the need for targeted interventions to improve the mental health of front-line healthcare professionals. Healthcare organizations must recognize the importance of fostering compassionate work environments that prioritize nurses’ spiritual and psychological well-being.