IntroductionThe coronavirus disease (COVID-19) swept the globe and harmfully influenced the mental health and behaviors of the college student population. This study aims to examine the prevalence and difference of mental health and the substance use problems of the Chinese college-age students studying in China and America (CSA) during the COVID-19 pandemic.MethodsOne thousand five hundred four students participated in this study. A total of 42.12% of students are enrolled in Chinese colleges, and 57.78% of students are enrolled in American colleges, aged 17–23 years (x¯±s = 19.90 ± 1.50). Binary logistic regression and independent t-test were used in this study to find the predictor variables and association among mental health, substance use problems, and student population.ResultsThe two student groups had a statistical difference in General Anxiety Disorder-7 scale, alcohol, medicines, drinks, drugs and cigarettes (p < 0.01). The students suffering depression problems from the two groups have statistical significance with drinks (odds ratio = 0.89, 95% confidence interval = 0.81–0.97, p < 0.05; odds ratio = 1.11, 95% confidence interval = 1.04–1.19, p < 0.01). CSA experiencing anxiety problem had a significant association with alcohol, drinks, cigarette, and desserts (p < 0.05).ConclusionThis is the first cross-sectional study focusing on the comparison of the Chinese college-age students' mental health and substance use problems who are studying in China and America during the pandemic. Our study revealed severe mental health and substance use problems in both student groups, particularly in the CSA during the COVID-19 pandemic. The findings of our study also highlight the evidence to find more interventions and preventions to solve the different mental health and substance use problems for college students.