Abstract Background Health benefits have been linked with physical activity (PA), as well as some domains of PA among youth (e.g. organized PA and active transport). However, less is known about whether some PA domains are more beneficial than others. There is also a lack of evidence about whether health outcomes are related to the composition of PA (i.e. the share of PA spent in different domains). This study aimed to identify: (1) how the absolute durations of organized PA, non-organized PA, active transport and active chores/work at 10-11y are individually associated with physical, psychosocial and total health-related quality of life (HRQOL) at 10-11y and 12-13y; and (2) how the domain-specific composition of PA at 10-11y is associated with HRQOL at 10-11y and 12-13y. Methods Data from the Longitudinal Study of Australian Children were used in cross-sectional (n ≥ 2730) and longitudinal analyses (n ≥ 2376). Measurement included the Pediatric Quality of Life Inventory (PedsQL™) for HRQOL domains and one-day time-use diaries (TUDs) for PA domains. Robust linear regression models were used, controlling for age, sex, pubertal status, socioeconomic position, body mass index and TUD context (season and school attendance). Compositional models additionally adjusted for total PA duration and longitudinal models controlled for baseline PedsQL™ scores. Results Non-compositional models indicated that the duration of organized PA, and to a lesser extent non-organized PA, were positively but weakly associated with some HRQOL outcomes at 10-11y. These trends were not reflected in longitudinal models, although a 30-min increase in non-organized PA per day did predict marginally better psychosocial HRQOL at 12-13y (+ 0.17%; 95%CI = + 0.03%, + 0.32%). Compositional models revealed that a 30-min increase in organized PA relative to other domains was positively but weakly associated with physical (+ 0.32%; 95%CI = + 0.01%, + 0.63%), psychosocial (+ 0.41%; 95%CI = + 0.11%, + 0.72%) and total HRQOL (+ 0.39%; 95%CI = + 0.12%, + 0.66%) at 10-11y. However, the overall PA composition at 10-11y was not related to HRQOL at 12-13y. Conclusions Non-compositional and compositional models generally concurred on the direction of cross-sectional and longitudinal relationships (and lack thereof) between PA domains and HRQOL outcomes. The strongest associations were cross-sectional between organized PA and HRQOL at 10-11y. However, all associations between PA domains and HRQOL outcomes were weak and may not be clinically meaningful.