Children's dietary habits can have a key role in contributing to an improvement in their Health-Related Quality of Life (HRQoL). This study aims to assess the connection between Mediterranean diet adherence and HRQoL in a sample of Greek students, utilizing data from the DIATROFI program. The parents of 3774 students (mean age 7.8 (2.6) years) reported their children's HRQoL and level of adherence to the Mediterranean dietary pattern at the beginning and end of the 2021-2022 school year. At baseline, most students' adherence was characterized as moderate (55.2%) or high (25.1%). Students with moderate or high adherence tο the Mediterranean diet were less likely to report a total HRQoL below the median at baseline (OR = 0.56, 95%CI = 0.44, 0.70), along with all its dimensions (physical, emotional, social, and school functions). A one-unit improvement in KIDMED score (beginning-end of schoolyear) was associated with the likelihood of an improvement in total HRQoL (beginning-end of schoolyear) (OR = 1.09, 95%CI = 1.02, 1.17), emotional (OR = 1.09, 95%CI = 1.02, 1.17), and social functions (OR = 1.13, 95%CI = 1.05, 1.22), but not with physical and school functions. The health benefits of the Mediterranean diet in children may not be limited to disease prevention but also extend to their overall wellbeing.