Objectives: This study aims to quantify the cross-sectional and prospective associations between quality of life (QoL) and moderate-to-vigorous physical activity (MVPA). Methods: This study was based on the Swiss children's Objectively measured PHYsical Activity cohort. The primary endpoint is the overall QoL score and its six dimensions. The main predictor is the average time spent in MVPA per day. Linear mixed effects and linear regression models respectively were used to investigate the cross-sectional and prospective associations between MVPA and QoL. Results: There were 352 participants in the study with complete data from baseline (2013-2015) and follow-up (2019). MVPA was positively associated with overall QoL and physical wellbeing (p = 0.023 and 0.002 respectively). The between-subject MVPA was positively associated with the overall QoL, physical wellbeing, and social wellbeing (p = 0.030, 0.017, and 0.028 respectively). Within-subject MVPA was positively associated with physical wellbeing and functioning at school (p = 0.039 and 0.013 respectively). Baseline MVPA was not associated with QoL 5 years later. Conclusion: Future longitudinal studies should employ shorter follow-up times and repeat measurements to assess the PA and QoL association.