This study conducted a comprehensive national assessment of COVID-19 vaccine hesitancy in the United States, using a multi-item questionnaire deployed online via mTurk and social media. The survey recruited 1878 U.S. adults, with the majority being female, White, non-Hispanic, married, full-time employed, and having a bachelor’s degree or higher. The results showed that 22% of participants were hesitant to get the COVID-19 vaccine, with lower education, income, and perceived infection risk being significant factors. Vaccine hesitancy was higher among African-Americans, Hispanics, those with children at home, rural dwellers, northeastern residents, and Republicans. Multiple regression analyses identified sex, education, employment, income, having children at home, political affiliation, and perceived infection risk as significant predictors of vaccine hesitancy. The study highlights the need for evidence-based communication, mass media strategies, and policy measures to address vaccine hesitancy and ensure equitable mass immunization.This study conducted a comprehensive national assessment of COVID-19 vaccine hesitancy in the United States, using a multi-item questionnaire deployed online via mTurk and social media. The survey recruited 1878 U.S. adults, with the majority being female, White, non-Hispanic, married, full-time employed, and having a bachelor’s degree or higher. The results showed that 22% of participants were hesitant to get the COVID-19 vaccine, with lower education, income, and perceived infection risk being significant factors. Vaccine hesitancy was higher among African-Americans, Hispanics, those with children at home, rural dwellers, northeastern residents, and Republicans. Multiple regression analyses identified sex, education, employment, income, having children at home, political affiliation, and perceived infection risk as significant predictors of vaccine hesitancy. The study highlights the need for evidence-based communication, mass media strategies, and policy measures to address vaccine hesitancy and ensure equitable mass immunization.