Childhood overweight and obesity have become a global public health problem that threatens children’s future health. The impaired influence of childhood overweight and obesity on their health-related quality of life (HRQOL) has been documented using clinical and population-based samples among children. Very few studies have analyzed socio-demographic and neighbourhood determinants of HRQOL and underlying influencing factors of diet quality and physical activity (PA) for HRQOL among primary school children. While the beneficial effects of school-based programs on promoting healthy behaviors and some aspects of health among children have been documented, the impact of such interventions on their HRQOL has yet to be evaluated. The purpose of the present study included: (1) to assess associations between socio-demographic and neighbourhood characteristics and the HRQOL among grade five students in Alberta; (2) to investigate how diet quality, PA and weight status correlate with their HRQOL; (3) to construct a scoring system for the EQ-5D-Y (youth) that can be used to derive health state index values for grade five students; and (4) to assess the influence of a school-based program promoting active living and healthy eating on HRQOL of the students. These objectives were addressed using population based data collected in 2008 and 2010 with the Raising Healthy Eating and Active Living Kids in Alberta surveys, and intervention data collected as part of the Alberta Project Promoting Active Living & Healthy Eating in Schools (APPLE Schools).