Background: Compassion fatigue is a well-documented consequence of prolonged occupational stress among healthcare professionals, particularly nurses working in high-demand settings such as oncology units. In a Muslim-majority context, spirituality and religious beliefs may serve as important psychological resources for coping with work-related stress. However, culturally tailored spiritual motivational interventions for oncology nurses remain underdeveloped. Objective: The current study aimed to validate the content of Islamic spiritual motivational messages developed to support Muslim oncology nurses experiencing compassion fatigue. Materials and Methods: A literature review informed the development of 75 religious and spiritually grounded motivational messages tailored to oncology nursing practice. Content validity was assessed using the Content Validity Index (CVI) and Content Validity Ratio (CVR) by a panel of six experts. Messages with CVI values below 0.78 and CVR values below 0.99 were excluded. Results: Sixty-three messages met the established content validity criteria. The overall CVI and CVR were 0.989 and 1, respectively, indicating excellent content validity. Conclusion: The findings support the relevance and clarity of Islamic spiritually grounded motivational messages as a culturally appropriate strategy to enhance professional quality of life and mitigate compassion fatigue among Muslim oncology nurses. Implication for Nursing: The study highlights the potential integration of motivational messages in routine nursing practice, particularly in oncology settings, where nurses face emotional challenges. Such spiritually sensitive approaches can enhance motivation, resilience, and job satisfaction, and should be considered in nursing leadership, education, and future intervention development.