Background: Health-related quality of life (HRQoL) allows knowing the subject’s feelings in distress and well-being, as well as perception of current and future health. Objective: To assess associations between health-related quality of life, fitness status, and adherence to the Mediterranean diet in Spanish children and adolescents. Methods: A cross-sectional study was carried out in a sample of 305 (47.2% women) children and adolescents aged between 8 and 16 years, in the primary and secondary schools of the province of Ávila (central Spain) (NCT05380674). Subjects were classified according to their quality of life: group 1 (highest quality of life) > group 2 (medium quality of life) > group 3 (lowest quality of life). Results: More participants in group 1 showed higher adherence to Mediterranean diet (70.8%) than other groups (group 2: 55.0%; group 3: 43.4%). It was less likely to find optimal levels of muscle strength as quality of life decreased (OR; 95% CI: group 2: 0.535; 0.303–0.955; and group 3: 0.424; 0.234–0.768). Similar trends were found for speed and agility, but only group 3 showed significant results (OR; 95% CI: group 3: 0.297; 0.162–0.545). Flexibility was also the worst in groups 2 and 3 (OR; 95% CI: G2: 0.403; 0.213–0.762; and group 3: 0.520; 0.282–0.958). Conclusion: High fitness status and adherence to the Mediterranean diet were associated with improved health-related quality of life in schoolchildren of central Spain.