This study sets out to understand the role of cultural worldviews, risk perceptions, and trust in scientists in impacting U.S. participants' support for COVID-19 mandatory vaccination. Results from an online survey (“N” = 594) suggest that stronger individualistic and hierarchical worldviews are associated with more perceived COVID-19 vaccination risks, less perceived COVID-19 vaccination benefits, and lower support for COVID-19 mandatory vaccination. Perceived benefits mediate the impact of cultural worldviews on support for COVID-19 mandatory vaccination. Trust in scientists moderates the relationship between cultural worldviews and perceived benefits of COVID-19 vaccination. Theoretical and practical implications of the findings are discussed.