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Aim: To describe positive and negative spiritual responses to providing COVID-related nursing care among nurses working in hospitals., Background: The COVID pandemic has intensified and publicised the threats to nurse well-being. Absent from the recommendations for promoting nurse well-being is recognition of how nurses' spirituality and/or religiosity is affected by the strain of COVID caring or how it may be affecting their well-being., Design: Cross-sectional, descriptive observational, mixed methods study., Methods: Data were collected from 523 registered nurses employed in three Southern California hospitals during March-May, 2022 when these hospitals' COVID case counts were <15%. Using Online survey methods, data were obtained using the Religious/Spiritual Struggles Scale-Short Form, Moral Injury Symptom Scale-Healthcare Professionals, Post-traumatic Growth Inventory and demographic and work-related items. STROBE guidelines for cross-sectional observational studies were observed., Results: The mean for religious/spiritual struggles was 1.98 (range of 1-5, comparable to a little bit). Although roughly half of the sample reported the struggles were not experienced/did not apply, 23%-36.5% reported experiencing these struggles at least somewhat. The most frequent struggle was to find ultimate meaning. The mean observed for moral injury was 6.5 (range of 1-10); applying established criteria indicated it was troubling for at least 50%. The mean for post-traumatic growth was 4 (on a scale of 0-6); using established criteria, 41% experienced PTG. Quantitative findings were illustrated by the qualitative responses that occasionally expressed spiritual tragedy and transformation concurrently., Conclusion: The professional work of nursing impacts nurses in invisible, spiritual ways that can be tragic and/or transformative., Relevance to Clinical Practice: Interventions to address nurses' mental health challenges must include attention to these invisible struggles. Nurses' mental health challenges must be met in part by addressing how they can surmount spiritual tragedy-and allow spiritual transformation., (© 2023 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)