Background <p>Childhood maltreatment has been associated with poorer family functioning among college students with major depressive disorder (MDD). Nonetheless, the specific pathway through which childhood maltreatment affects family functioning remains unclear, particularly concerning the potential mediating role of interpersonal functioning and the moderating role of illness-related family burden. Guided by the Double ABC-X framework, which explains family adaptation through stressors, resources, and coping processes, this study examined whether interpersonal functioning mediated the association between childhood maltreatment and family functioning in Chinese college students with MDD. This study also examined whether illness-related family burden moderated the association between childhood maltreatment and family functioning.</p> Methods <p>A cross-sectional study was conducted with 525 Chinese college students with major depressive disorder (MDD). Students completed the Family Assessment Device (FAD), Childhood Trauma Questionnaire (CTQ), and Interpersonal Relationship Comprehensive Diagnostic Scale (IRCDS). Caregivers completed the Illness-related Family Burden Scale. Descriptive statistics and Spearman correlation analyses were conducted in R based on the five imputed datasets. Mediation and moderation analyses were conducted in Mplus 8.3. Parameter estimates, standard errors, and 95% confidence intervals were pooled across imputed datasets according to Rubin’s rules.</p> Results <p>Childhood maltreatment, interpersonal dysfunction, illness-related family burden, and poorer family functioning scores were positively correlated with each other. Interpersonal functioning mediated the association between childhood maltreatment and family functioning, and the indirect effect was significant (<i>β</i> = 0.035, 95% CI [0.013, 0.057], <i>p</i> &lt; 0.01). Illness-related family burden moderated the association between childhood maltreatment and family functioning (<i>β</i> = −0.121, 95% CI [− 0.194, − 0.049], <i>p</i> &lt; 0.01). Childhood maltreatment was associated with poorer family functioning in both the low and high illness-related family burden group. Compared with students in the high illness-related family burden groups (simple slope = 3.073, <i>t</i> = 10.349, <i>p</i> &lt; 0.001), students in the low illness-related family burden groups showed a stronger association between childhood maltreatment and poorer family functioning (simple slope = 4.387, <i>t</i> = 14.160, <i>p</i> &lt; 0.001).</p> Conclusion <p>Among Chinese college students with MDD, childhood maltreatment impaired family functioning through reduced interpersonal functioning, and illness-related family burden negatively moderated the association between childhood maltreatment and family functioning. These findings extend the application of the Double ABC-X framework to MDD in Chinese college students and highlight the need for future stratified interventions, such as enhancing interpersonal skills, strengthening family communication, and expanding community-based and healthcare support, to improve family adaptation.</p>