Introduction: The outbreak of coronavirus disease has negatively impacted college students' mental health across the world. In addition, substance abuse also is trouble among these students. This study aims to find the gender difference in Chinese international college students' mental health and substance abuse during the COVID-19 pandemic.Method: We conducted an online survey using PHQ-9, GAD-7, and several questions related to substance abuse frequency, self-injury, and suicidal thoughts, 535 male and 475 female Chinese international college students whose ages ranged from 18 to 23 years old (x = 20.19, SD = 1.50) were recruited during the epidemic. We utilized t-test and binary logistic regression in our study to find out the difference and statistical significance between substance abuse issues and mental health problems across gender.Results: Both male and female Chinese international college students had statistical significance with self-injury ideas and behaviors (t = −2.21, p < 0.05). Furthermore, the male college students with anxiety problems had positive statistical significance with medicine (OR = 3.47, 95%CI = 1.45–8.30, p < 0.01) and negative statistical significance with drinks (OR = 0.23, 95%CI = 0.08–0.65, p < 0.01). While for female college students with an anxiety problem, they had positive statistical significance with medicine (OR = 4.88, 95%CI = 1.53–15.57, p < 0.01), drugs (OR = 4.48, 95%CI = 1.41–14.25, p < 0.05) and cigarettes (OR = 6.63, 95%CI = 1.95–22.57, p < 0.01) and negative statistical significance with drinks (OR = 0.18, 95%CI = −0.05 to 0.65, p < 0.01).Conclusion: This is the first cross-sectional study focusing on the Chinese international college students' mental health and substance abuse problems during the COVID-19 pandemic. We found that Chinese international college students' mental health and substance abuse situation has been negatively influenced during this period. In addition, the self-injury ideas and behaviors also showed a high tendency for these students. The findings of our study also highlight the need to find more interventions and preventions to solve the different mental health and substance abuse problems for college students, especially for female Chinese international college students.