Coronavirus disease 2019 (COVID-19) continues to ravage world economies, and with its recent mutations, countries worldwide are finding ways of ramping up their vaccination programmes. This cross-sectional design study, therefore, examined the predictors of COVID-19 stress and COVID-19 vaccination acceptance among adolescents in Ghana. A total of 817 participants were conveniently selected to respond to measures on fear of COVID-19, perceived stigma from COVID-19, self-stigma from COVID-19, believing COVID-19 information, COVID-19 infection prevention behaviours, COVID-19 stress, and COVID-19 vaccination acceptance. It was found that females believed COVID-19 information and accepted COVID-19 vaccination more than males did. Moreover, there were significant relationships between the majority of the COVID-19-related variables. Furthermore, fear of COVID-19, self-stigma from COVID-19, and COVID-19 infection prevention behaviours were found to be significant predictors of COVID-19 stress. Additionally, believing COVID-19 information, danger and contamination fears (a subscale of COVID-19 stress), and traumatic stress (a subscale of COVID-19 stress) were significant predictors of COVID-19 vaccination acceptance. These findings imply that different factors influence different COVID-19 variable. Therefore, careful considerations and research should be employed by health authorities and policymakers in preparing COVID-19 information to target different age groups and for different COVID-19 purposes.