The study starts from the consideration that healthcare buildings (hospitals, polyclinics, nursing homes) constitute a significant building and plant heritage. These are strategic infrastructures that are highly energy-intensive due to their age and technological obsolescence. From the analysis of the existing situation, a conceptual framework is proposed that can improve the design of healthcare buildings in an innovative way and with high safety and sustainability features. The goal is to obtain, through a holistic approach, a conceptual and operational reference model that allows the design of cognitive health buildings capable of interacting dynamically and predictively with the users of the structure (health professionals and patients), providing and optimizing the conditions of well-being and improving the provision of health and social care services, with a view to sustainability through Digital Twins systems supported by Artificial Intelligence for the optimal governance of technologies and systems to achieve the best environmental sustainability through the constant measurement of the Smart Readiness Indicator of healthcare buildings. The Case Study is the application of the conceptual model to the design of a cognitive healthcare building in Italy (Lecce ASL), which will provide for the advanced integration of all systems under a single control system; the management of Micro Grids consisting of the various sources of supply provided for the services of the structure; control logics based on Digital Twin systems, Artificial Intelligence, Deep Learning; BIM-based data sharing and management platform throughout the entire building lifecycle; advanced energy monitoring systems.