The COVID-19 pandemic has affected populations globally, including Ghana. Knowledge of the COVID-19 disease, and the application of preventive public health interventions are pivotal to its control. Besides a lockdown, measures taken against the spread of the virus include the wearing of face masks, social distancing, regular hand washing with soap and, more recently, vaccination against the virus. In order to establish a possible link between the knowledge of the disease and compliance with preventive measures, including vaccination, a cross-sectional study employing an interview-structured questionnaire was conducted in six regions of Ghana (n = 1560). An adequate level of knowledge of COVID-19 (69.9%) was reported. The linear multiple regression analysis further explicated the differences in the knowledge of COVID-19 among the respondents by their knowledge of cholera and influenza (adjusted R-Square = 0.643). Despite this profound knowledge of the illness, two thirds of the respondents were unwilling to follow basic preventive measures and only 35.3% were willing to be vaccinated. Amazingly, neither knowledge of COVID-19 nor the socio-demographic characteristics had any meaningful influence on the practice of preventive measures. Personal attitude leading to efficient public compliance with preventive measures, therefore, is a critical issue demanding special attention and effective interventions by the government and locals with authority to curb the spread of the pandemic which surpasses the traditional channels of public health communication. This includes a roll-out of persuasion, possibly including public figures and influencers, and in any case, a balanced and open discussion addressing the acceptance of the COVID-19 vaccine in order to avoid new variants and comparable problems currently facing many countries of Western Europe. Indeed, a profound hesitancy against vaccination may turn African countries such as Ghana for many years into hotspots of new viral variants.