Although a major public health and social concern globally, limited data exist on substance use and their effects among adolescents living in low- and middle-income countries. This study evaluated the relationships between alcohol/drug use and quality of life (QOL) among adolescents in general populations from India, Indonesia, Nigeria, Serbia, Turkey, Bulgaria, and Croatia. The sample included 2,393 adolescents. The Pediatric Quality of Life Inventory (PedsQL) was used for QOL assessments, the Strengths and Difficulties Questionnaire (SDQ) was used for mental health problems, and the CRAFFT self-report questionnaire was administered for eliciting alcohol/drug use. Alcohol/drug use was significantly associated with lower levels of QOL. In particular, substance use among older male adolescents, adolescents with overt psychopathology, or adolescents in lower socioeconomic status was associated with greater reductions in levels of QOL.