BACKGROUND: Monitoring public confidence and hesitancy is crucial for the COVID-19 vaccine rollout. Social media listening (infoveillance) can not only monitor public attitudes on COVID-19 vaccines but also assess the dissemination of and public engagement with these opinions. OBJECTIVE: This study aims to assess global hesitancy, confidence, and public engagement toward COVID-19 vaccination. METHODS: We collected posts mentioning the COVID-19 vaccine between June and July 2020 on Twitter from New York (United States), London (United Kingdom), Mumbai (India), and Sao Paulo (Brazil), and Sina Weibo posts from Beijing (China). In total, we manually coded 12,886 posts from the five global metropolises with high COVID-19 burdens, and after assessment, 7032 posts were included in the analysis. We manually double-coded these posts using a coding framework developed according to the World Health Organization's Confidence, Complacency, and Convenience model of vaccine hesitancy, and conducted engagement analysis to investigate public communication about COVID-19 vaccines on social media. RESULTS: Among social media users, 36.4% (571/1568) in New York, 51.3% (738/1440) in London, 67.3% (144/214) in Sao Paulo, 69.8% (726/1040) in Mumbai, and 76.8% (2128/2770) in Beijing indicated that they intended to accept a COVID-19 vaccination. With a high perceived risk of getting COVID-19, more tweeters in New York and London expressed a lack of confidence in vaccine safety, distrust in governments and experts, and widespread misinformation or rumors. Tweeters from Mumbai, Sao Paulo, and Beijing worried more about vaccine production and supply, whereas tweeters from New York and London had more concerns about vaccine distribution and inequity. Negative tweets expressing lack of vaccine confidence and misinformation or rumors had more followers and attracted more public engagement online. CONCLUSIONS: COVID-19 vaccine hesitancy is prevalent worldwide, and negative tweets attract higher engagement on social media. It is urgent to develop an effective vaccine campaign that boosts public confidence and addresses hesitancy for COVID-19 vaccine rollouts.