In the context of the formidable challenges posed by the COVID-19 pandemic, healthcare professionals coped in various ways. This cross-sectional survey study sought to examine the protective role of satisfaction with life, sense of coherence, and resilience in the relationship between depression, social support, fear of COVID-19, and perceived vulnerability to disease among nurses in South Africa. Participants were a convenience sample of nurses ( n = 264) working at four South African hospitals in the Western Cape. Data were collected by means of an electronic survey and analysed using structural equation modelling. Participants completed a comprehensive battery of psychological measures. We found that while higher levels of fear of COVID-19 robustly predicted depressive symptomology among nurses, factors such as sense of coherence, and social support emerged as protective resources. These protective factors have the potential to alleviate the mental health impacts of pandemic-related stressors among nurses.