The project focuses on the energy upgrading of the General Hospital “Papageio” in Thessaloniki, with a useful surface area: 62 950 m², from category C to category B+ of the Energy Performance of Buildings Regulation (KENAK). The proposed interventions plan primarily meets the hospital’s energy needs. It exhausts the energy saving potential, leading to the hospital’s “energy homes”. In addition, based on its new energy profile, interventions of Renewable Energy Sources (RES) systems are planned, complementary to the three-generation heat/cooling system operating at the hospital’s premises, with the aim of creating a zero-emission building. The combination of a plan of actions that are best practices and a tool that allows energy planning, the establishment and, above all, the monitoring of indicators of the hospital’s energy behaviour ensures as far as possible that its operation is fully controlled and efficient. The proposed interventions plan, once implemented, will achieve primary energy savings of 9.2 % compared to the current state of operation, a significant proportion for a hospital of the size of the Papageorgiou Hospital, while the reduction of emitted pollutants, which will occur as a result of the implementation of the energy upgrading plan, is estimated at 1 808 tn CO2/year.