Mitigating seismic risk for critical facilities is crucial for governments, decision-makers, researchers, society, and the economy in earthquake-prone regions in Europe and worldwide. The paper discusses some essential concepts and methods for developing and implementing a real-time risk assessment methodology through a specific testbed example in light of an engineering-based seismic risk reduction approach for critical buildings. The goal is to demonstrate that real-time seismic risk assessment of a target building could be feasible by combining a calibrated earthquake early warning system (EEWS) with the knowledge of structure-specific fragility curves evaluated with the aid of well-designed structural monitoring arrays. The whole approach is illustrated for a school building located in Thessaloniki city center. The target school is instrumented with permanent and temporary monitoring arrays using commercial accelerometric/velocimeter stations and special in-house developed low-cost Micro-Electro-Mechanical Systems (MEMS). Structural health monitoring (SHM) allows identifying the dynamic characteristics of the building and, finally, generate structure-specific fragility functions, which may differ from generic ones. Past and current seismic events recorded on the regional seismic network and locally on sensors installed at the school building are used for the calibration and validation of the regional EEWS in order to reduce the rate of false or missed alarms. The refined structure-specific fragility functions are incorporated into the central database and used by the developed real-time risk assessment software for the promptly prediction of seismic damages and losses. The performance of the whole system is effectively checked for a strong seismic event by reproducing the Mw 6.5, 1978 Thessaloniki destructive earthquake based on 3D physics-based numerical simulations.