Background: Childhood nutrition plays an important role in the promotion of long-term health. Introducing solid foods in alignment with the Mediterranean Diet during weaning fosters a preference for healthy foods early in life. However, access to nutritious diets remains a challenge in underserved communities. Scampia, a socioeconomically disadvantaged district in Naples, Italy, exemplifies a community where barriers to healthy eating persist. This research reports a trial protocol that plans for a study to evaluate the impact of the Mediterranean Diet on child health and to establish preventive strategies for chronic diseases. Methods: The PEMED (PrEventive effect of MEditerranean Diet in Children) trial is a Bayesian Sequential Pragmatic Cluster Randomized Clinical Trial. Family Pediatricians (FPs) are randomized to deliver either Mediterranean Diet-based dietary guidance starting at weaning or standard dietary practices using typical baby foods. Children will be followed up for six years, with regular assessments of growth, microbiome composition, and adherence to the Mediterranean Diet, using validated tools. Interim analyses will be conducted at three-year intervals to evaluate the efficacy and monitor adverse events. Saliva and stool samples will be collected for genetic and microbiome analyses, and adherence will be monitored through quarterly dietary recalls and biomarkers. Results: This trial will consider Italy's established FP network for implementing innovative dietary intervention in a real-world setting. Conclusions: This study will address nutritional disparities in the underserved Scampia community and provide a scalable model for early dietary interventions. The results will shed light on the role of the Mediterranean Diet in improving childhood health and informing public health strategies globally.