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Objective: The present study assessed the public's perception and Knowledge about COVID-19 and factors that could affect vaccine acceptability in Ghana. Design: We carried out a cross-sectional population-based study. A structured questionnaire was used to capture data on socio-demographic information, knowledge, and the public's perception of COVID-19 infection, as well as COVID-19 vaccine acceptability from consented participants. Factors affecting vaccine acceptability in Ghana were explored. Robust ordinary least square linear regression analysis was adopted to assess factors associated with vaccine acceptability. Setting: Five communities (Labone, Lartebiorkoshie, Old Fadama, Chorkor, and Ashiyie) in Accra in the Greater Accra district were selected. Participants: WHO modified cluster-sampling method was applied to select households of 997 participants in the five communities. Results: Most respondents were males (57.6%), and the median age of participants was 30 years. The study participants demonstrated a good knowledge of COVID-19 and had high perceptions of the COVID-19 pandemic. The results revealed that the highest educational level, marital status, self-rated Knowledge of COVID-19, Knowledge of COVID-19 definition, Knowledge of COVID-19 symptoms, and perception of the COVID-19 pandemic were significantly associated with vaccine acceptability. Self-reported impact of COVID-19 lockdown/movement restrictions on agriculture and job as a source of livelihood was associated with vaccine acceptability. Conclusion: Higher subjective and objective knowledge of COVID-19 increases vaccine acceptability scores significantly thus, education on COVID-19 and the vaccination against SARS-CoV-2 infection must be intensified to improve vaccine acceptability in Ghana, especially among those with lower educational backgrounds. [ABSTRACT FROM AUTHOR]