A significant portion of the building stock in European seismic regions was constructed without incorporating energy-efficient or anti-seismic design principles. To address the urgent need for deep renovation, the e-SAFE H2020 research project has developed innovative retrofit technologies tailored for reinforced concrete (RC) framed buildings. These solutions include prefabricated timber-based panels that provide both structural reinforcement and thermal insulation. Applied to the building’s outer envelope, these panels significantly enhance seismic resilience and energy efficiency. In addition to the envelope improvements, the e-SAFE approach integrates advanced full-electric systems to meet energy demands for domestic hot water, space heating, and cooling. These combined technologies have been implemented in a pilot building in Catania, Sicily (Southern Italy). This paper presents the final design outcomes of the core e-SAFE technological components and outlines the application strategies used to validate the retrofit intervention in the pilot project.