In the wide context of facility management, several processes, such as operations, maintenance, retrofitting, and renovations, ensure that buildings comply with the principles of efficiency, cost-effectiveness, and indoor comfort. Apart from ordinary operation, facility management is responsible for the renovation of and long-term performance improvement of building facilities. In such a scenario, the cyber—physical system (CPS) paradigm with holonic architecture, which is the focus of this study, can successfully guide the operation management and long-term refurbishment processes of buildings. Analogous to the manufacturing field, the developed CPS maximizes holons’ self-configuration and self-organization and overall throughput effectiveness metrics to detect the best corrective actions toward system improvements. Consequently, suggestions and lessons learned from the evaluation of building efficiency are redirected to the building information model. Hence, the digital model acts as a repository of currently available equipment for operations management and the history of diagnoses that support decision-making during the maintenance, retrofitting, and renovation processes. Evidently, the repeated detection of a specific issue, which is unaffected by operations management, should be considered an opportunity to act and enhance the performances of existing building components. Similar to a goods-producing industry, the building management system developed in this study applies the aforementioned methodology to provide services related to indoor comfort and building health. This approach indicates that a method for automatic real-time diagnosis is tested in a case study consisting of a multi-use and large public building. The current paper, which is an extended version of the one presented in the Creative Construction Conference 2018, deepens the decision support tool and the supervision policy. Moreover, the developed system is contextualized by providing an example of use case and highlighting the step forward in the field of smart buildings.