COV-2 SARs has disproportionately affected low- and middle-income countries such as Ghana, where the healthcare system was not prepared enough to provide care, drugs, and equipment. This study was carried out to assess predictors of COVID-19 vaccine acceptance among health professionals in the Bono region of Ghana. A facility-based cross-sectional study was conducted among 424 health professionals recruited through simple random sampling. Univariate and multivariate logistic regression models were utilized to identify the predictors of COVID-19 vaccine acceptance presented as an odds ratio (OR) with a 95% confidence interval (CI). All respondents had heard about the COVID-19 vaccine. The most common source of information was the media (45.8%). The proportion of health professionals who accepted the COVID-19 vaccine was 73.6%. Among those who did not take the vaccine, 64.3% were willing to take it in the future. The key predictors of taking the COVID-19 vaccine included: age 25 to 45 years (AOR = 1.96, 95% CI: 1.14–3.35), age older than 45 years (AOR = 5.30, 95% CI: 2.59–10.87), males (AOR = 4.09, 95% CI: 2.34–7.15), Christians (AOR = 3.10, 95% CI: 1.44–7.72), and at least three years of experience (AOR = 1.74, 95% CI: 1.033–2.93). Reasons for not taking vaccines included: vaccines were rapidly developed and approved (41.0%), immediate side effects (39.2%), and unforeseen future effects (37.5%). This study showed that most participants had received their first dose of COVID-19 vaccination, and most of those hesitant about the vaccine were willing to receive it in the future. This is a positive finding for policy makers since it reflects that fewer resources will be needed for behavioural change initiatives. In addition, it would present a chance to focus on minority individuals who are unwilling to take the vaccine and offer targeted community mobilisation.