Background: Intensive Care Unit (ICU) and Emergency Department (ED) nurses have faced several moral challenges during the COVID-19 pandemic. The factors associated with nurses’ moral distress (MD) can vary depending on the cultural context. Objectives: This study aimed to determine the relationship between MD, spiritual well-being (SWB), and moral intelligence (MQ) of nurses in ICUs and EDs during the COVID-19 pandemic. Methods: This descriptive cross-sectional study was conducted in 2020. The data were collected using self-report questionnaires, including those for personal and professional profiles, Corley’s Moral Distress Scale-Revised, Paloutzian & Ellison’s Spiritual Well-being, and Lennick & Kiel’s Moral Intelligence. Of the 543 nurses working in the ICUs and EDs of hospitals in Zanjan Province (Iran), 370 participants were selected by census sampling. Results: The study results indicated that 90.8% of nurses experienced high MD. The results of the partial correlation test showed no statistically significant relationship between nurses' MD and their SWB or MQ (P > 0.001). Nurses with an associate's degree (P = 0.019) and those working in the EDs (P = 0.001) and the COVID-19 care center hospital (P = 0.001) had higher levels of MD. Religious well-being and the educational level of nurses could predict only 2.5% of the variations in nurses’ MD. Conclusions: This study showed that SWB and MQ of nurses are not related to nurses’ MD, unlike environmental factors. It is recommended that managers provide more support to reduce nurses’ MD in critical situations, such as during the COVID-19 pandemic.