BACKGROUND: Health care workers (HCWs) are among the high-risk groups in contracting and dying from COVID-19. World Health Organization estimates that over 10,000 HCWs in Africa have been infected with COVID-19 making it a significant occupational health hazard to HCWs. In Ghana, over 100 HCWs have already been infected and dozen others died from the virus. Acceptability and uptake of the COVID-19 vaccine is therefore critical to promote health and safety of HCWs as the country battles out of a third wave of the pandemic. OBJECTIVE: The study sought to ascertain the correlates of HCWs likelihood of participating in a COVID-19 vaccine trial and accepting the vaccine when given the opportunity. METHODS: The study was a web-based cross-sectional survey among HCWs (n = 1605) in all sixteen (16) administrative regions in Ghana. Data were analyzed with STATA statistical analysis software (version 14). Chi-square (X2) and Fisher's exact tests were used to test for differences in categorical variables; bivariate probit regression analysis with Average Marginal Effect (AME) was employed to ascertain the determinants of HCWs' likelihood of participating in a COVID-19 vaccine trial and taking the vaccine. RESULTS: It was found that 48% of HCWs will participate in a COVID-19 vaccine trial when given the opportunity; 70% will accept the COVID-19 vaccine; younger HCWs (AME = 0.28, SE = 0.16, p < 0.1), non-Christians (AME = 21, SE = 0.09, p < 0.05) and those who worked in faith-based health facilities (AME = 18, SE = 0.07, p < 0.05) were more likely to participate in a COVID-19 vaccine trial. Female HCWs (AME = - 11, SE = 0.04, p < 0.05) and those with lower educational qualification were less likely to accept a COVID-19 vaccine (AME = - 0.16, SE = 0.08, p < 0.1). Reasons cited for unwillingness to participate in a COVID-19 vaccine trial or uptake the vaccine were mainly fear, safety concerns, mistrust, uncertainty, spiritual and religious beliefs. CONCLUSIONS: Acceptance of the COVID-19 vaccine appear to be high among HCWs; conversely, willingness to volunteer for the vaccine trial was low. Continuous targeted and integrated public health education for HCWs will enhance vaccine acceptability to promote safety and population health in the global south as Ghana intensifies efforts to produce COVID-19 vaccines locally.