Health related quality of life’s (HRQoL) different domains of functioning can serve as a good prognosticator of later life’s outcomes for children and adolescents. Understanding associated factors is crucial for promoting better health and life satisfaction. This study aimed to investigate the impact of socio-economic status (SES), physical activity (PA) and cardio-fitness on the Health-Related Quality of Life (HRQoL) in 224 Italian early adolescents attending secondary school in the Emilia-Romagna region located in northern Italy. The present cross-sectional study included measures of SES, demographic factors, cardio-fitness measures and self-reported PA levels. In a multivariate model, younger students and females reported higher HRQoL (β=-0.139, P<.05, 95% CI: -0.254 – -0.023 and β=0.142, P<.05, 95% CI: 0.011 – 0.273 respectively). Having both parents employed and having higher familiar educational status resulted in higher HRQoL. Greater engagement in routine PA was positively associated with HRQoL (β=0.429, P<.001, 95% CI: 0.304 – 0.554). Endurance (speed) was positively associated with HRQoL (β=0.221, P<.01, 95% CI: 0.087 – 0.355) and students with longer times on the shuttle run reported less HRQoL (β=-0.207, P<.01, 95% CI: -0.337 – -0.077). Findings reinforced the importance of promoting regular PA among students and addressing SES disparities to improve HRQoL. The study suggests a focus on expanding research measures and evaluating targeted PA interventions for a more comprehensive understanding of children’s well-being. These findings highlight the crucial roles of demographic, PA and cardio-fitness measures in child’s HRQoL, thus providing relevant information for stakeholders who work in the education, public health, and health policy sectors.