<p>This study aimed to investigate the correlation between depression and school adjustment among medical college students and examine loneliness as a mediator and family functioning as a moderator in the relationship. In November 2022, a stratified cluster sample of 1866 medical college students from two colleges was surveyed. The 2-item Patient Health Questionnaire (PHQ-2), the Family Adaptation Partnership Growth Affection and Resolve index (APGAR), the short-form Loneliness Scale (ULS-8), and the Student Adaptation to College Questionnaire (SACQ) were used to evaluate depressive symptoms, individual subjective satisfaction with family functioning, loneliness, and students’ adjustment to school, respectively. The PROCESS macro program was used to examine the moderated mediation model. Results showed inverse correlations between school adjustment and both depression and loneliness, and a positive correlation with family functioning. Loneliness partially mediated the effect of depression on adjustment. Family functioning played a moderating role in the relationships between depression and loneliness, and between loneliness and adjustment. Specifically, as family functioning improved from low to high levels, the positive effect of depression on loneliness intensified, as did the negative impact of loneliness on adjustment. However, family functioning did not moderate the relationship between depression and adjustment. Results highlight that early identification and intervention for depression and loneliness may help prevent school maladjustment in college freshmen, particularly for students from highly functioning families. It offers a nuanced perspective on mental health interventions.</p>