No study has examined the potential moderating role of recreational substance use in the relationship between the Mediterranean diet (MedDiet) and academic performance. The aim of this study was to test the potential moderating role of recreational substance use (i.e., alcohol, tobacco, and cannabis) in the association of adherence to the MedDiet with academic performance among adolescents. This cross-sectional study included a sample of 757 adolescents (55.6% girls) aged 12–17 years from theValle de Ricote(Region of Murcia). The Region of Murcia is an autonomous community of Spain located in the southeast of the Iberian Peninsula, along the coast of the Mediterranean Sea. Adherence to the MedDiet was assessed by the Mediterranean Diet Quality Index for Children and Teenagers (KIDMED). Recreational substance use (i.e., tobacco, alcohol, cannabis) was self-reported by adolescents. Academic performance was assessed by the school records at the end of the academic year. The relationship between adherence to the MedDiet and academic performance was moderated by both tobacco and alcohol use (for grade point average and all school records). In conclusion, higher adherence to the MedDiet was related to greater academic performance in adolescents, but recreational substance use could moderate this association.