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Background: Vaccines are effective and reliable public health interventions against viral outbreaks and pandemics. However, hesitancy regarding the Coronavirus disease (COVID-19) vaccine is evident worldwide. Therefore, understanding vaccination-related behavior is critical in expanding the vaccine coverage to flatten the infection curve. This study explores the public perception regarding COVID-19 vaccination and identifies factors associated with vaccine hesitancy among the general adult populations in six Southeast Asian countries. Methods: Using a snowball sampling approach, we conducted a descriptive cross-sectional study among 5260 participants in Indonesia, Malaysia, Myanmar, Philippines, Thailand, and Vietnam between February and May 2021. Binary logistic regression analysis with a backward conditional approach was applied to identify factors associated with COVID-19 vaccine hesitancy. Results: Of the total, 50.6% were female, and the median age was 30 years (range: 15–83 years). The majority of the participants believed that vaccination effectively prevents and controls COVID-19 (81.2%), and 84.0% would accept COVID-19 vaccines when they become available. They agreed that health providers' advice (83.0%), vaccination convenience (75.6%), and vaccine costs (62.8%) are essential for people to decide whether to accept COVID-19 vaccines. About half (49.3%) expressed their hesitancy to receive the COVID-19 vaccines. After adjustment for other covariates, COVID-19 vaccine hesitancy was significantly associated with age, residential area, education levels, employment status, and family economic status. Participants from Indonesia, Myanmar, Thailand, and Vietnam were significantly more likely to express hesitancy in receiving COVID-19 vaccines than those from Philippines. Conclusions: In general, participants in this multi-country study showed their optimistic perception of COVID-19 vaccines' effectiveness and willingness to receive them. However, about half of them still expressed their hesitancy in getting vaccinated. The hesitation was associated with several socioeconomic factors and varied by country. Therefore, COVID-19 vaccination programs should consider these factors essential for increasing vaccine uptake in the populations. [ABSTRACT FROM AUTHOR]