Aim Within the context of increasing mental distress noted since the beginning of the COVID19 pandemic, the study aims at analysing the relationship between mental health, vaccine distrust and vaccine hesitancy in South Africa. Subject and methods The study uses nationally representative panel data of 3241 individuals interviewed prior to and during the COVID19 pandemic. The study uses a range of regression techniques including logit, mediation and gradient-boosted causal mediation models to identify the causal relationship while accounting for selection bias. Results The results of multivariate logit regression reveal that vaccine distrust is the most important predictor of vaccine hesitancy [Coeff: 3.420, CI 3.122, 3.717]. Mental distress is not found to be a significant driver in a fully specified logit model, pointing to the need to analyse the pathways through which mental distress impacts vaccine hesitancy. The mediation regression undertaken for this purpose finds that the mental distress has a positive and significant association with vaccine distrust [Coeff: 0.027, CI: 0.0029, 0.052]. The increased vaccine distrust in turn results in increased vaccine hesitancy [Coeff: 0.661, CI: 0.611, 0.711]. The results of mediation regression therefore indicate strong and significant mediation effects, whereby mental health effects vaccine hesitancy through the mediating variable of vaccine distrust. These results are robust to the gradient boosted causal mediation model which establishes strong and significant indirect effects [Coeff: 0.015, CI: 0.01, 0.019], whereby mental health effects vaccine hesitancy through the mediating variable of vaccine distrust. Conclusion The study concludes that mental health impacts on vaccine intention through the mediating role of vaccine distrust. The findings indicate that individuals at high risk of depression are more concerned regarding the safety of vaccines, which in turn feeds into vaccine hesitancy. Therefore, depressive symptoms impact on vaccine hesitancy through the mediating factor of vaccine distrust.