Mass vaccination against COVID-19 is the best method to ensure herd immunity in order to curb the effect of the pandemic on the global economy. It is therefore important to assess the determinants of COVID-19 vaccine acceptance and hesitancy on a global scale. Factors were recorded from cross-sectional studies analyzed with t-Test, ANOVA, correlation, and meta-regression analyses and synthesized to identify global trends in order to inform policy. We registered the protocol (ID: CRD42022350418) and used standard Cochrane methods and PRISMA guidelines to collect and synthesize cross-sectional articles published between January 2020 and August 2023. A total of 67 articles with 576 studies from 185 countries involving 3081,766 participants were included in this synthesis. Global COVID-19 vaccine acceptance was 65.27% (95% CI; 62.72–67.84%), while global vaccine hesitancy stood at 32.1% (95% CI; 29.05–35.17%). One-Way ANOVA showed that there was no significant difference in the percentage Gross Domestic Product spent on vaccine procurement across the World Bank income levels (p < 0.187). There was a significant difference of vaccine acceptance (p < 0.001) and vaccine hesitancy (p < 0.005) across the different World Bank Income levels. World Bank income level had a strong influence on COVID-19 vaccine acceptance (p < 0.0004) and hesitancy (p < 0.003) but percentage Gross Domestic Product spent on vaccine procurement did not. There was no correlation between percentage Gross Domestic Product spent on vaccine procurement and COVID-19 vaccine acceptance (r = −0.11, p < 0.164) or vaccine hesitancy (r = −0.09, p < 0.234). Meta-regression analysis showed that living in an urban setting (OR = 4.83, 95% CI; 0.67–212.8), rural setting (OR = 2.53, 95% CI; 0.29–119.33), older (OR = 1.98, 95% CI; 0.99–4.07), higher education (OR = 1.76, 95% CI; 0.85–3.81), and being a low income earner (OR = 2.85, 95% CI; 0.45–30.63) increased the odds of high COVID-19 vaccine acceptance. Factors that increased the odds of high COVID-19 vaccine hesitancy were no influenza vaccine (OR = 33.06, 95% CI; 5.03–1395.01), mistrust for vaccines (OR = 3.91, 95% CI; 1.92–8.24), complacency (OR = 2.86, 95% CI; 1.02–8.83), pregnancy (OR = 2.3, 95% CI; 0.12–141.76), taking traditional herbs (OR = 2.15, 95% CI; 0.52–10.42), being female (OR = 1.53, 95% CI; 0.78–3.01), and safety concerns (OR = 1.29, 95% CI; 0.67–2.51). We proposed a number of recommendations to increase vaccine acceptance and ensure global herd immunity against COVID-19.