Purpose. Psychological resilience plays an important role in relieving the psychological distress. However, little is known about its underlying mechanisms. Mental health literacy, an important way to promote mental health, may mediate the effect of psychological resilience on psychological distress. This study aimed to explore the relationship between mental health literacy, psychological resilience, and psychological distress and explore the mediating effect between psychological resilience and psychological distress. Design and Methods. A cross-sectional study design was used. A total of 627 medical students were selected from one university. An electronic questionnaire was administered to collect information on the level of mental health literacy, psychological resilience, and psychological distress. Pearson’s correlation analysis was used in analyzing the relationship, and the Bootstrap method was used to test the mediating effects. Findings. Psychological distress significantly negatively correlated with mental health literacy and psychological resilience ( P < 0.001 ). The indirect effect of mental health literacy accounted for 50.43% of the total effect between psychological resilience and psychological distress. Practical Implication. Psychological resilience decreased the level of psychological distress, and this relationship was partially mediated by mental health literacy. These findings showed that efforts aimed at enhancing the mental health literacy may prevent or reduce the prevalence of psychological distress symptoms among college students.