Objectives: This paper examines the relationship between health literacy and mental well-being of school staff during distressful times. It examines the mediating roles of work-related stress, health-protective behaviours (i.e., attitudes about vaccination), and sense of coherence in the relationship between health literacy and mental well-being. Study design: A cross-sectional survey. Methods: Data were derived from 440 school staff who participated in a study on Health Literacy and Well-being of School Staff across all schools in Hong Kong. Structural Equation Modelling was used for path analysis. Results: Most (64.9 %) of the school staff had limited health literacy (i.e. problematic or inadequate). The mean score of their mental well-being was 51.4 out of 100 (±20.8), with around 18 % of them at risk of depression. Health literacy was not directly associated with mental well-being. Instead, it predicted mental well-being through work-related stress (B = 0.130, p = 0.036) and adoption of health-protective behaviours (B = 0.376, p = 0.021). Conclusion: While health literacy may not directly influence the mental well-being of school staff, it has a critical role in safeguarding mental well-being in times of distress by shaping positive attitudes towards protective health measures and managing sources of work stress.