Highlights: ► Little is known about the impacts of sibling caretaking on mental health of caretakers. ► We examined associations between sibling caretaking and depression among adolescents. ► Increased levels of depressive symptoms are associated with sibling caretaking. ► Increased levels of depressive symptoms are also associated with poor school performance.Abstract: In many resource-poor countries, home-based care for young children is crucial. Yet little has been known about the negative impacts of sibling caretaking on mental health conditions of adolescent student caretakers. This study explored associations between sibling caretaking, school performance, and depression among 1943 students randomly selected from 11 junior high and high schools in Cambodia. The Asian Adolescent Depression Scale was used to measure depressive symptoms. In bivariate analyses, we used χ2 test or Fisher’s exact test for categorical variables and t-test or one-way analysis of variance for continuous variables. Multiple linear regression models were then constructed. Of total, 60.1% of our participants took care of their younger sibling(s) regularly during the past one year. The number of siblings under their care ranged from one to nine, and the time they spent for sibling care ranged from one to 10h per day. After adjustment, increased levels of depressive symptoms remained significantly associated among boys with sibling caretaking (p<0.001), as well as poor school performance (p=0.001) and perceived likelihood of dropping out of school in the near future (p=0.002). Among girls, increased levels of depressive symptoms retained their significant association with sibling caretaking (p<0.001); also poor school performance (p<0.001). Sibling care responsibility might have negative impact on school performance and the mental health condition of adolescent caretakers.