Background A major component of rolled-out COVID-19 pandemic response and preparedness is the administration of vaccines. Globally, resistance towards vaccination programs are well known and documented. This study sought to evaluate the effects of general vaccine health perceptions and the confidence in COVID-19 vaccine safety towards uptake in Ghana. MethodsA cross sectional online survey involving 620 Ghanaians was conducted. The data was subjected to both descriptive (frequency, percentages, and chi-square tests) and inferential (nested binary logistic regression) analyses. Results The preliminary findings showed that 80.32% of participants believed that vaccines were healthy and 73.06% had confidence in a COVID-19 vaccine safety, although 81.19% of the respondents were particularly concerned about the source of the vaccine. Other evidence revealed that 78.55% and 71.45% of respondents indicated their willingness for mandatory and voluntary COVID-19 vaccine uptake or shot respectively. In all operationalized regression models, Ghanaians who believed that vaccines are healthy and those who had confidence in a COVID-19 vaccine safety were more likely to take a mandatory or voluntary COVID-19 vaccine compared to those who thought and believed otherwise. ConclusionIndividual preferences and/or intentions toward COVID-19 vaccine uptake and uptake route (i.e., mandatory, voluntary) were influenced by multifaceted determinants: biosocial (age, marital status, education), socio-cultural (religion) and contextual (geographical zone, source of vaccine as a concern) factors. To consolidate and possibly increase vaccine uptake in response to the COVID-19 pandemic in Ghana, health education and promotion programs should aim at creating awareness on the benefits of vaccine uptake while addressing the health and safety concerns on the potential side effects through evidence-based community messaging from credible sources. It is important to show specific commitment to transparency and reliable information to build public trust by decision-makers.