Background <p>On February 6, 2024, the South Korean government’s decision to increase the medical school admission quota triggered a nationwide collective leave of absence involving &gt; 95% of medical students. We aimed to assess the mental health status of medical students on leave and to identify factors that could mitigate psychological distress.</p> Methods <p>A cross-sectional online survey was conducted between August 12 and August 23, 2024. A total of 203 responses were collected and evaluated. Depression and stress were assessed using the Patient Health Questionnaire-9 (PHQ-9) and the Korean version of the Brief Encounter Psychosocial Instrument (BEPSI-K), respectively. Additionally, factors that may contribute to depression, such as external stressors, time spent on social media, and time engaged in exercise, were examined. Predictors of depression (PHQ-9 ≥ 10) were identified using univariate and multivariate logistic regression analyses. A mediation analysis was conducted to investigate the direct effect of stress on depression and the indirect effects mediated by social media use and exercise.</p> Results <p>Depression was observed in 42.4% (<i>n</i> = 86) of participants (PHQ-9 ≥ 10) and showed a higher prevalence among female students and those in earlier academic years. Logistic regression analysis identified significant associations between the PHQ-9 score and BEPSI-K score, social media use, and total exercise time. A mediation analysis clarified the relationship between stress (as indicated by higher BEPSI-K scores) and depression (as indicated by higher PHQ-9 scores), as well as the exacerbating effect of social media use and the protective effect of exercise.</p> Conclusions <p>The mental health of medical students on collective leave of absence in South Korea is a critical concern. Continuous monitoring and interventions are essential, with strategies such as increasing physical activity and reducing social media use showing potential for mitigating psychological distress.</p>