Previous research has demonstrated that becoming vaccinated with the Coronavirus vaccine may lower mental distress. However, it remains uncertain whether this relationship holds amid concerns of vaccine side effects and doubts of the vaccine's protective capabilities. We presented three studies that showed how vaccine confidence negatively influences the relationship between vaccine uptake and mental distress. Using two-way fixed effects regression models, Study 1 analyzes longitudinal survey of respondents from Los Angeles County in the US, while Study 2 uses the same analytical strategy but generalises findings by analysing longitudinal data of participants across all 50 US states. Main results of both studies show that (i) vaccination uptake is linked with reduced mental distress among individuals with high vaccine confidence (ii) vaccine uptake has no effect on mental distress among individuals with low vaccine confidence. Lastly, Study 3 applies multilevel analysis to a large-scale pseudo-panel study of 15 developed countries. Results for the third study corroborate finding (i) but not (ii) in that the multinational study finds that vaccine uptake is actually associated with higher mental distress among individuals with low vaccine confidence. In sum, our paper shows that the palliative effect of vaccination on mental health only exists when vaccine confidence is high. Results are mixed on whether vaccination affects mental distress when individual vaccine confidence is low.