Adolescent nutrition and healthy dietary patterns, particularly the Mediterranean diet (MD), have been associated with improved health status and decreased risk of various chronic and metabolic diseases later in life. The aim of this study was to evaluate the impact of the Mediterranean food choices on lipid and glycemic metabolic profile in the total population and in adolescents grouped according to their physical activity (PA) levels at the time of recruitment (T0) and after six months from the administration of a personalized Mediterranean meal plan (T1). As part of the DIMENU study, 85 adolescents underwent measurements of lipid and glucose metabolic profile at T0 and T1. Using three positive items from KIDMED test related to the consumption of typical Mediterranean food (olive oil, fish, and nuts) and three negative items on dietary habits (going to fast-food, consuming biscuits, and candies), we categorized adolescents into six sets in which biochemical parameters were analyzed. In the total sample, significant reductions in serum total cholesterol, LDL, and glucose concentrations were observed for all the sets over the study period. Notably, active subjects, who had a better serum metabolic profile, showed significant improvements of glycemic control after 6 month follow up, while in sedentary adolescents and in those performing moderate PA significant reduction in glycemia, total cholesterol, and LDL was found in all sets. In conclusion, adopting the typical Mediterranean food choices led to a significant reduction in glucose and lipid profile in healthy adolescents, thus making the MD and PA a winning combination for health status.