The paper proposes a novel holistic methodology to design the refurbishment of educational buildings in heating dominated climates of Mediterranean regions. The proposed approach is based on the solution of a constrained multi-objective problem by means of genetic algorithm implemented in EnergyPlus. The optimization process regards energy, and environmental objectives as well as the occupants’ thermal comfort. The case study of a student dormitory of Campobasso (Italian backcountry city) is proposed. The optimal set of energy efficiency measures shows approximately 55% of the energy saved during the heating season and 24% during cooling season.