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To examine mental health status, COVID-19 vaccine intention and barriers among college students in the U.S. Participants: Students (n = 337) registered at a large public university in 2021. Methods: Cross-sectional survey data were collected online and analyzed using independent samples t test, chi-square test, and one-way ANOVA. Results: Compared to male students, females reported greater anxiety (p < 0.05) and fear (p < 0.01). Hispanic participants reported increased anxiety level and the least positive pandemic coping strategies (both p < 0.05) across the ethnic groups. Black students were the racial group with the lowest trust in the safety and effectiveness of COVID-19 vaccine (p < 0.05). Vaccine intention was positively correlated with factors such as vaccine safety measures, and perceptions toward vaccination (both p < 0.001). Conclusions: These gender- and ethnicity- based mental health struggles should be addressed immediately for better health and vaccine promotion outcomes amid the COVID-19 pandemic.