Background <p>This study aimed to examine the relationships among college students’ depression, academic stress, and parent-child relationship quality, and to inform the development of effective depression prevention strategies.</p> Methods <p>Participants were recruited from two sources: college students at a university in Hubei Province (via the Hubei College Student Health Survey, HCSHS) and the China Family Panel Studies (CFPS). The study employed multiple linear regression analysis to explore the associations between these variables.</p> Results <p>A total of 871 college students were included in the final analysis, comprising 569 from HCSHS and 302 from CFPS. The sample yielded a mean depression score of 14.08 ± 3.90 and a mean perceived academic stress score of 3.19 ± 0.96. Multiple linear regression analyses revealed that academic stress (<i>β</i> = 0.22, <i>P</i> &lt; 0.001) and parent-child relationship quality (categorized as average or distant: <i>β</i> = 0.37, <i>P</i> &lt; 0.001) emerged as key predictors of depression in college students. In addition, a significant interaction effect was observed between academic stress and parent-child relationship quality on depression in college students (<i>β</i> = -0.24, <i>P</i> = 0.02).</p> Conclusion <p>Among college students, both academic stress and average or distant parent-child relationships were found to significantly increase the risk of depression, with a significant interaction observed between these two factors. Specifically, a close parent-child relationship was found not to exert a stress-buffering effect against academic stress; rather, it was associated with heightened sensitivity to such stress, thereby amplifying its adverse impact on depressive symptoms.</p>