The aim of this cross-sectional study was to analyze the association between adherence to the Mediterranean diet (MedDiet) and its dietary components and health-related quality of life (HRQoL) in a sample of Spanish adolescents. A total sample of 634 adolescents was included (mean age: 13.96 ± 1.54 years; 56.9% girls). The Mediterranean Diet Quality Index in children and adolescents (KIDMED) and the KIDSCREEN-10 were used to assess adherence to the MedDiet and its components and HRQoL, respectively. Linear regression was applied to estimate the association between overall adherence to the MedDiet and HRQoL. Cluster analysis was used to establish subgroups according to different patterns of MedDiet component consumption. Higher overall adherence to the MedDiet was significantly associated with greater HRQoL (unstandardized beta coefficient [β] = 0.329; 95% CI: 0.108, 0.550; p = 0.004), even after adjustment for sociodemographic, physical and lifestyle covariates (β = 0.228; 95% CI: 0.007, 0.449; p = 0.043). When different clusters were established according to similar features of MedDiet component consumption, the cluster with a higher percentage of individuals who skipped breakfast had significantly lower scores on the HRQoL scale (p < 0.05)  Conclusions: Our findings highlight the relevance of considering the specific patterns of food group consumption and MedDiet-related behaviors and not just the overall measure of MedDiet adherence for promoting HRQoL in adolescents. What is Known: • Previous studies have shown that some lifestyle behaviors, such as dietary habits, could be associated with health-related quality of life. • According to our results, higher adherence to the Mediterranean diet pattern was associated with greater health-related quality of life in adolescents. What is New: • Skipping breakfast seems to have a crucial role in health-related quality of life among adolescents. • These results could lead to the development of more specific dietary strategies for increasing health-related quality of life in adolescents.