Structural equation modelling (SEM) was applied to data from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort to help elucidate causal pathways to decreased health-related quality of life (HRQoL) in children with juvenile idiopathic arthritis (JIA).Based on published literature and clinical plausibility, a priori models were constructed with explicit root causes (disease activity, treatment intensity) and mediators (pain, disease symptoms, functional impairments) leading to HRQoL measured by the Quality of my Life (QoML) scale and the Juvenile Arthritis Quality of Life Questionnaire (JAQQ), at five disease stages: 1) diagnosis, 2) 3-9 months after diagnosis, 3) flare, 4) remission on medications, 5) remission off medications. Following SEM, a posteriori models were selected based on data fit and clinical plausibility.We included 561, 887, 137, 186 and 182 patients at each stage, respectively. In a posteriori models for active disease stages, paths from disease activity led through pain, functional impairments, and disease symptoms, directly or through restrictions in participation, to decreased QoML scores. Treatment intensity had detrimental effects through psychosocial domains; while treatment side effects had a lesser role. Pathways were similar for QoML and JAQQ, but JAQQ models provided greater specificity. Models for remission stages were not supported by the data.Our findings support disease activity and treatment intensity as root causes of decreased HRQoL in children with JIA, with pain, functional impairments and participation restrictions as mediators for disease activity; and psychosocial effects and side effects as mediators for treatment intensity.