Politics is ubiquitous in public health, but vaccines had never been weaponized to instill distrust to gain political advantage. In pandemic and post-pandemic scenarios, populist political parties could use vaccine-related issues to generate distrust in evidence-based knowledge. Therefore, some questions arise. What impact could populist political parties impinge on vaccination uptake rates through sowing political discontent? What could the medical institutions do to avoid the adverse effects that these political strategies could infringe? For answering these research questions, we first hypothesized that vaccine uptake was negatively associated with distrust in the institutions. Furthermore, we analyzed whether populism mediates this relationship. In doing so, we hypothesized a positive association between distrust and populism, because populists, mainly fueled by politically discontent citizens, offer hope of a better future, blaming their misfortune on the actions of the elite. Additionally, we hypothesized that those citizens with a higher level of political dissatisfaction, following the claims of the populist political parties, will have lower vaccine uptake results, because they will be discouraged from making the efforts to counter the pandemic. Based on a survey carried out by the European Commission that covered 27 E.U. + U.K. countries (totaling 27,524 respondents), this paper proves that an individual’s political discontent fully mediates the relationship between distrust in institutions and vaccine uptake. Targeting the vaccine-hesitant population is quite convenient for populists because they only need to convince a minority of citizens not to be vaccinated to achieve their destabilizing goals. New outbreaks will appear if the minimum herd immunity coverage is not reached, reinforcing a vicious circle of distrust in elites, in consequence. For tackling this matter, recommendations are given to institutional managers from a social marketing standpoint.