Background:Multicultural comparative studies have recently increased scientific knowledge base regarding the mental health of diverse populations. This cross-cultural study was cross-sectionally designed to assess differences in the prevalence and predictors of clinically significant depressive symptoms between Chinese and Malawian children.Methods:A total of 478 children (237 Chinese and 241 Malawians) were randomly recruited in the study. The participants completed a Children Depression Inventory in the dimensions of Negative Mood, Interpersonal Problems, Ineffectiveness, Anhedonia, and Negative Self- Esteem. They further provided demographic and family structure information. Data were analyzed by Student’s t-test, Chi-square test, and logistic regression.Results:The prevalence of clinically significant depressive symptoms was 16% and 12.4% for Chinese and Malawian study participants, respectively. Multivariate logistic regression analysis showed that fighting among siblings (adjusted odds ratio [aOR] = 4.1, 95% CI, 3.5–5.9), fighting among children and parents (aOR = 7.7, 95% CI, 4.6–9.8) and living with father only (aOR = 4.1, 95% CI, 3.4–6.7) were significant predictors of clinically significant depressive symptoms among Chinese study participants. On the other hand, clinically significant depressive symptoms were predicted by employment status of a mom only among Malawian study participants (aOR = 3.0, 95% CI, 2.3–5.9).Conclusions:We conclude that diverse cultures affect children’s mental health differently and this cluster of children has a noticeable amount of depressive symptoms that in the least requires further diagnosis and preventive measures.