Background: Health-related quality of life (HRQoL) has become a significant outcome in assessing interventions in the pediatric population and could be influenced by diet patterns. The Mediterranean diet (MD) pattern has been related to multiple positive health outcomes, including decreased cardiovascular risk and better mental health. We aimed to evaluate the association between MD adherence and HRQoL in children and adolescents. Methods: The literature search was conducted in PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Ovid-MEDLINE databases from inception to May 2022. Two researchers independently checked titles and abstracts, evaluated full-text studies, extracted data, and appraised the risk of bias using the Newcastle–Ottawa Scale (NOS). Results: Eleven studies (1 longitudinal and 10 cross-sectional), totaling 6,796 subjects, were included. Ten studies assessed MD adherence with KIDMED index, and one assessed MD adherence with Krece Plus test, while all included studies assessed HRQoL with a KIDSCREEN test. All studies analyzed the association between MD adherence and HRQoL with linear regression, and eight used adjusted models. Five studies found a significant positive association of MD adherence with HRQoL, with β-values ranging from 0.13 to 0.26. Two found a nonsignificant positive relationship, while one found a negative association. According to the NOS criteria, the risk of bias assessment showed four studies with a low risk of bias and seven with a high risk of bias. Conclusion: Our findings suggest a positive correlation of MD adherence with HRQoL in children and adolescents. However, future research is needed to strengthen the evidence of this relationship. Trial registration: CRD42021236188 (PROSPERO).