BACKGROUND: Physical functioning and psychological resilience in adulthood is shaped during adolescence. Self-reported health-related quality of life (HRQoL) assessments during this life phase are important first-hand accounts of their well-being. This study aimed, firstly, to identify differences in HRQoL according to gender, ethnicity, socio-economic status and weight status; and secondly, to examine associations between weight status and HRQoL among an urban sample of multi-ethnic adolescents in Kuala Lumpur, Malaysia. METHODS: A cross-sectional study involving 652 adolescents (aged 13 years) was conducted in Kuala Lumpur. Weight and height were measured. Body mass index z-scores were categorized according to the International Obesity Task Force criteria. HRQoL was assessed using the Malay version of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales. Univariate analyses of differences in HRQoL according to gender, ethnicity (Malays, Chinese and Indians), maternal education level and weight status were performed. Complex samples general linear model was used to examine the associations between HRQoL and weight status, adjusted for confounders. RESULTS: Female adolescents reported significantly lower emotional functioning scores (mean, 95% confidence interval: 59.25, 57.33-61.17). When the three main ethnic groups were studied, Malay adolescents scored significantly lower emotional functioning scores (59.00, 57.13-60.87) compared with their Chinese peers. Adolescents with tertiary-educated mothers reported lower emotional functioning scores (57.45, 53.85-61.06) compared with those with primary-educated mothers. Obese adolescents reported poorer HRQoL scores with significantly impaired physical and social functioning after controlling for confounders. CONCLUSIONS: These findings detected disparities in HRQoL among the adolescents when gender, ethnicity, maternal education level and weight status were considered. Further studies should address these health inequalities by implementing gender-specific and culturally appropriate measures to attain optimal well-being and avoid potential burden of disease.