Background: Health-related quality of life (HRQoL) in childhood is a multidimensional construct with many sub dimensions of subjective experience, including physical activity (PA), psychological well-being, social interaction, and school performance, that represents a fundamental health outcome to assess a child’s physical and psycho-social functioning. Our study aims to explore the potential predictors of children’s health-related quality of life, using a convenience sample from the Imola Active Break Study (I-MOVE), considering demographic, anthropometric measures, PA level measured by Actigraph accelerometers, parent-reported/self-reported HRQoL, and body image. Methods: A cross-sectional analysis was conducted among 151 primary school children in Italy. HRQoL was assessed using the Italian version 4.0 of the Paediatric Quality of Life (PedsQL) questionnaire. Results: Children who spent more time partaking in moderate PA were associated with a higher total PedsQL score (p < 0.03). Mother’s body mass index (BMI) was the only variable statistically significant associated with the physical health domain of PedsQL. Parent’s proxy-report perception concerning children’s psychosocial health was statistically relevant. The children’s gender, age, and BMI had no association with any of the HRQoL outcomes. Discussion: Parent proxy-report psychosocial health and mother’s BMI should be considered as predictors of HRQoL for the psychosocial and physical domain. PA should be implemented in order to improve the HRQoL of primary school children.