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<h4>Background</h4>Mass vaccination campaigns have significantly reduced the COVID-19 burden. However, vaccine hesitancy has posed significant global concerns. The purpose of this study was to determine the characteristics that influence perceptions of COVID-19 vaccine efficacy, acceptability, hesitancy and decision making to take vaccine among general adult populations in a variety of socioeconomic and cultural contexts.<h4>Methods</h4>Using a snowball sampling approach, we conducted an online cross-sectional study in 20 countries across four continents from February to May 2021.<h4>Results</h4>A total of 10,477 participants were included in the analyses with a mean age of 36±14.3 years. The findings revealed the prevalence of perceptions towards COVID-19 vaccine's effectiveness (78.8%), acceptance (81.8%), hesitancy (47.2%), and drivers of vaccination decision-making (convenience [73.3%], health providers' advice [81.8%], and costs [57.0%]). The county-wise distribution included effectiveness (67.8-95.9%; 67.8% in Egypt to 95.9% in Malaysia), acceptance (64.7-96.0%; 64.7% in Australia to 96.0% in Malaysia), hesitancy (31.5-86.0%; 31.5% in Egypt to 86.0% in Vietnam), convenience (49.7-95.7%; 49.7% in Austria to 95.7% in Malaysia), advice (66.1-97.3%; 66.1% in Austria to 97.3% in Malaysia), and costs (16.0-91.3%; 16.0% in Vietnam to 91.3% in Malaysia). In multivariable regression analysis, several socio-demographic characteristics were identified as associated factors of outcome variables including, i) vaccine effectiveness: younger age, male, urban residence, higher education, and higher income; ii) acceptance: younger age, male, urban residence, higher education, married, and higher income; and iii) hesitancy: male, higher education, employed, unmarried, and lower income. Likewise, the factors associated with vaccination decision-making including i) convenience: younger age, urban residence, higher education, married, and lower income; ii) advice: younger age, urban residence, higher education, unemployed/student, married, and medium income; and iii) costs: younger age, higher education, unemployed/student, and lower income.<h4>Conclusions</h4>Most participants believed that vaccination would effectively control and prevent COVID-19, and they would take vaccinations upon availability. Determinant factors found in this study are critical and should be considered as essential elements in developing COVID-19 vaccination campaigns to boost vaccination uptake in the populations.