Purpose Based on the interpersonal theory of depression and resilience framework theory, this study tested the association between interpersonal sensitivity and depression in college students in the context of the COVID-19 pandemic. Additionally, the mediating role of resilience and the moderating role of the COVID-19 lockdown were investigated. Methods A total of 5193 South Chinese college students (M=19.27, SD = 1.18) were included in the study. According to which campus they were living on, the subjects were categorized as members of a lockdown group or a nonlockdown group. They completed the interpersonal sensitivity subscales of the Symptom Checklist 90 (SCL-90), Beck Depression Inventory (BDI), and Connor-Davidson Resilience Scale (CD-RISC). SPSS 26.0 statistical software was used to analyse the descriptive statistics, reliability, and correlation. Specifically, a moderated mediation model was analysed by multivariate logistic regression. Results Interpersonal sensitivity was significantly associated with depression ( r = 0.517, p < 0.01), which was mediated by resilience ( β = 0.12, 95% CI = [0.10, 0.13]). Lockdown status was shown to have a moderating effect on the relationship between resilience and depression ( β = 0.03, t = 2.71, p < 0.01). Conclusion The high levels of interpersonal sensitivity displayed by South Chinese college students caused low resilience and then facilitated depression. The COVID-19 lockdown strengthened the effect of low resilience on depression. Lower resilience was more strongly associated with higher depression for students under lockdown conditions compared to students who were not in lockdown.