Background: Quality of life (QOL) is a universally accepted concept for measuring the impact of different aspects of life on general well-being. Adaptation of existing QOL instruments to local cultures has been identified as a better strategy than development of new ones. Aims: To translate and adapt the Paediatric Quality of Life Inventory Version 4.0 Generic Core Scales (PedsQL) to the Yoruba language and culture and to test the psychometric properties of the adapted instrument among adolescents. Methods: Psychometric properties including internal consistency reliability, construct and factorial validity of the Yoruba version of PedsQL were evaluated using standard procedures. Results: The self report and proxy scales of the Yoruba PedsQL were developed with good cultural relevance and semantic/conceptual equivalence. Results from 527 adolescents revealed a Cronbach’s coefficient which exceeded 0.7 for internal consistency reliability for all scores. The healthy subjects reported higher PedsQL scores than those with mental health and physical problems, which confirmed construct validity. Confirmatory factor analysis revealed a good model fit for the Psychosocial Health score, but not for the other measures. Conclusions: The Yoruba PedsQL is culturally appropriate and with good internal consistency, reliability and construct validity. More work is needed regarding its factorial validity.