To date, we know little about COVID-19-related health literacy among school leaders, particularly in East Asia. The present study aimed to assess the level of COVID-19-related health literacy and associated factors (vaccine hesitancy, self-endangering behaviour, and work satisfaction) among school leaders in Hong Kong. A cross-sectional study of 259 school leaders was carried out during the COVID-19 pandemic between April 2021 and February 2022. COVID-19-related health literacy using HLS-COVID-Q22, three subscales of self-endangering work behaviour scales (i.e., “extensification of work”, “intensification of work” and “quality reduction”), and two dimensions of Burnout Assessment Tool (BAT) (i.e., psychosomatic complaints and exhaustion) were used. The study employed independent sample t-test, ANOVA, and multilinear regression models. The findings show that more than half (53.7%) of school leaders had insufficient health literacy. Participants with insufficient health literacy scored significantly higher in the following factors: exhaustion related to work situation (p = 0.029), psychosomatic complaints (p < 0.001), attitude about vaccination (i.e., less agree with vaccination) (p < 0.001), level of informing on COVID-19 related information (i.e., felt less informed) (p < 0.001), and level of confusion about COVID-19-related information (i.e., felt more confused) (p < 0.001). In a linear regression model predicting attitude about coronavirus vaccination, age (β, −0.188, 95% CI, −0.024, −0.005, p = 0.002) and health literacy (β, −0.395, 95% CI, −0.716, −0.361, p < 0.001) were the negative predictors, F(5, 214) = 11.859, p < 0.001. For the linear regression model adjusted for sex and age for predicting health literacy, the model was insignificant. Despite being a highly educated group, this study reveals that one in two Hong Kong school leaders have insufficient health literacy. Inadequate health literacy was strongly associated with a negative attitude about vaccination, low information, and confusion about COVID-19-related information. Additionally, insufficient health literacy was associated with the two secondary symptoms of burnouts. The study highlights an urgent need to develop intervention programmes to promote the COVID-19-specific as well as overall health literacy of the school leaders.