Health-Related Quality of Life (HRQoL) is gaining attention in children and adolescents because it is an important outcome of their health status and well-being. Therefore, it is important to identify determinants for HRQoL. Currently, there is scarce and mainly cross-sectional evidence on the relationship between adherence to the Mediterranean diet and HRQoL in children and adolescents. Therefore, the objective of the present study was to assess the prospective association between adherence to the Mediterranean diet and HRQoL in Spanish children. The study was carried out in 1371 children aged 8 to 10 from different Catalan elementary schools with a medium follow-up of 15 months. The KidMed and KIDSCREEN-10 questionnaires were used to assess the relationship between diet and HRQoL, respectively. The KidMed score at baseline was positively associated with HRQoL (β = 0.320; 95% CI 0.101–0.540) after adjusting for confounders. Additionally, the logistic regression analysis showed positive associations between baseline consumption of fruit, vegetables, pulses, and high adherence to the Mediterranean diet and HRQoL at follow-up (p < 0.05 for all) while the consumption of fast-food, pasta or rice, baked good or pastries, and sweets were negatively correlated (p < 0.05 for all) with HRQoL at follow-up. In conclusion, adherence of the Mediterranean diet was predictive for HRQoL in Spanish children, but further prospective studies are needed to confirm this result.