Body image can predict health-related quality of life (HRQoL) in adolescent girls through self-esteem and psychological well-being. Additionally, depression is a significant predictor of adolescents’ HRQoL and is associated with body image. Therefore, we investigated whether the relationship between body image and HRQoL in adolescent girls is moderated by depression. In this cross-sectional study, adolescent girls’ body image, depression, and HRQoL (n = 385, age: 12–15 years) were measured through self-report questionnaires. Multiple regression and simple slope analyses were conducted to examine the moderating effect of depression. Body image was positively correlated with HRQoL, whereas depression was negatively correlated with body image and HRQoL. Body image, depression, and their interaction explained 44.9% of the variance in HRQoL. Simple slope analysis showed that a more positive body image was associated with higher HRQoL among adolescent girls without depressive symptoms, but was not significantly related to HRQoL for adolescents with depressive symptoms. The moderating effect of depression was confirmed. In conclusion, screening for depression is recommended for adolescent girls prior to implementing body image interventions in schools and the community that are aimed at improving HRQoL. Furthermore, health care providers in schools and the community should provide psychological support for depression along with body image interventions to improve the HRQoL of girls in schools and the community. In particular, for girls with depressive symptoms, depression management should be conducted beforehand.