Vaccination has emerged as the most cost-effective public health strategy for maintaining population health, with various social and economic benefits. These vaccines, however, cannot be effective without widespread acceptance. The present study examines the effect of media attention on COVID-19 vaccine hesitancy by incorporating fear of COVID-19 as a mediator, whereas trust in leadership served as a moderator. An analytical cross-sectional study is performed among rural folks in the Wassa Amenfi Central of Ghana. Using a questionnaire survey, we were able to collect 3079 valid responses. The Smart PLS was used to estimate the relationship among the variables. The results revealed that media attention had a significant influence on vaccine hesitancy. Furthermore, the results showed that fear of COVID-19 played a significant mediating role in the relationship between media and vaccine hesitancy. However, trust in leadership had an insignificant moderating relationship on the fear of COVID-19 and vaccine hesitancy. The study suggests that the health management team can reduce vaccine hesitancy if they focus on lessening the negative impact of media and other antecedents like fear on trust in leadership.