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Introduction: As they are satisfied with life, nurses who demonstrate spiritual intelligence and well-being at work are tremendous assets to an organisation. This study aimed to determine the mediating effect of spiritual intelligence on the well-being and life satisfaction of nurses in the context of COVID-19. Methods: This research employed a cross-sectional study design. It was conducted in the Hail region of Saudi Arabia. The participants were government hospital nurses who were chosen using a multi-stage sampling method. A total of 1121 (75% response rate) nurses participated in the study. Data gathering was conducted from July to September 2022. Results: The life satisfaction level of the participants was deemed positive. Their well-being was better (10/15), and they rated high in spiritual intelligence (90/120). Life satisfaction had a strong association with well-being (r = 0.640, p < 0.001), but a weak association with spiritual intelligence (r = 0.391, p < 0.001). In comparison, well-being had a moderate association with spiritual intelligence (r = 0.551, p < 0.001). The direct effect of well-being on spiritual intelligence was positive and significant (β = 0.7817, p < 0.0001), and that of spiritual intelligence on life satisfaction was positive and significant (β = 0.1082, p = 0.0257). The direct effect of well-being on life satisfaction was also positive and significant (β = 1.5985, p < 0.0001). Conversely, well-being had an indirect impact on life satisfaction (β = 0.0846), and this effect was significant. Overall, the impact of well-being on life satisfaction was positive and significant (β = 1.6831, p < 0.0001). Conclusion: The nurses in this study were deemed satisfied, to have better well-being, and better spiritual intelligence. Life satisfaction has a strong association with well-being but a weak one with spiritual intelligence, while well-being has a moderate association with spiritual intelligence. Overall, spiritual intelligence was found to have a mediating effect on the relationship between well-being and life satisfaction. These findings suggest that an increase in spiritual growth can serve as the foundation for people to live better and more integrated lives.