OBJECTIVE To investigate the independent and combined effects of lifestyle behaviors, including physical activity, sedentary behavior, sleep duration and food intake, in the health-related quality of life (HRQoL) of Brazilian adolescents. METHODS Cross-sectional school-based study, with the participation of 306 adolescents aged 14 to 18 years. A questionnaire was applied with structured questions to collect lifestyle behaviors data. Perception of the HRQoL was identified using the Kidscreen-27. The study used covariance analysis and linear regression models for statistical analysis. RESULTS Adolescents who reported ≤ 2 hours/day of screen-based sedentary behavior and sleep duration equivalent to 8-10 hours/night presented significantly higher HRQoL. Adolescents who reported joint adherence ≥ 3 healthy lifestyle behaviors demonstrated approximately two [OR=2.12] to three times [OR=3.04] more chance of presenting higher perceptions of HRQoL. CONCLUSIONS Although healthy lifestyle behaviors had a positive independent effect on HRQoL, joint adherence to healthy behaviors enhances the cumulative effect.