What Shapes Quality of Life in Youth? A Multidimensional Approach from Lifestyle to Residential Context—Cor-School Study

<b>Background</b>: Health-related quality of life is a key indicator of well-being that integrates physical, emotional, and social dimensions. Identifying its determinants during childhood and adolescence is essential to guide effective health promotion strategies. <b>Objective</b>: To analyze the association between health-related quality of life and demographic, anthropometric, biochemical, lifestyle, and environmental variables in school-aged children and adolescents. <b>Methods</b>: A cross-sectional study was conducted during the 2023-2024 academic year in northeastern Spain. A total of 571 children and adolescents participated in the study (mean age = 11.64 ± 1.64 years), of whom 254 were girls (44.48%). Health-related quality of life was assessed using the Revised Children's Quality of Life Questionnaire (KINDL-R), a validated instrument for assessing perceived well-being in pediatric populations. Independent variables included waist-to-height ratio, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, adherence to the Mediterranean diet, weekly physical activity, sleep quality, and residential context (i.e., large urban areas, small urban areas, and municipalities). Multiple linear regression analysis was performed to explore the associations. <b>Results</b>: Older age was associated with lower health-related quality of life (β = -1.07; 95% CI: -1.61 to -0.53; <i>p</i> < 0.001). In contrast, better adherence to the Mediterranean diet (β = 0.72; 95% CI: 0.09 to 1.37; <i>p</i> = 0.023), better sleep quality (b = -2.48; <i>p</i> < 0.001), and participants living in cities and large urban areas reported compared to those in municipalities were associated with higher HRQoL (<i>p</i> < 0.05), with moderate effect sizes. No significant associations were found for sex, waist-to-height ratio, cholesterol levels, or physical activity. <b>Conclusions</b>: This study highlights the importance of adopting a multidimensional approach to promote health-related quality of life in young populations, addressing dietary habits, sleep quality, and environmental factors within health promotion strategies.