Adolescence is the potential period for growth and optimal functioning, but developmental issues like time of transition from childhood to adulthood will create stress and affect the adolescent’s quality of life (QOL). However, there is a lack of research tool for measuring adolescent’s QOL in Malaysia. The aim of the study was to determine the validity and reliability of the self-report Malay version of the pediatric QOL (PedsQL™) 4.0 Generic Core Scales in assessing the QOL of Malaysian adolescents. A cross-sectional study design using the 23-item self-report Malay version of the PedsQL 4.0 Generic Core Scales was administered on a convenient cluster sampling (n = 297 adolescent) from a secondary school. The internal consistency reliability had Cronbach’s α values ranging from .70 to .89. Factor analysis reported a six-factor structure via principal axis factor analysis. In conclusion, the self-report Malay version of the pediatric QOL 4.0 Generic Core Scales is a reliable and valid tool to measure the QOL of multiethnic Malaysian adolescents.