In order to shed light on the seismic response of complex industrial plants, advanced finite element models should take into account both multicomponents and relevant coupling effects. These models are usually computationally expensive and rely on significant computational resources. Moreover, the relationships between seismic action, system response and relevant damage levels are often characterized by a high level of nonlinearity, which requires a solid background of experimental data. Vulnerability and reliability analyses both depend on the adoption of a significant number of seismic waveforms that are generally not available when seismic risk evaluation is strictly site-specific. In addition, detection of most vulnerable components, i.e., pipe bends and welding points, is an important step to prevent leakage events. In order to handle these issues, a methodology based on a stochastic seismic ground motion model, hybrid simulation and acoustic emission is presented in this paper. The seismic model is able to generate synthetic ground motions coherent with site-specific analysis. In greater detail, the system is composed of a steel slender tank, i.e., the numerical substructure, and a piping network connected through a bolted flange joint, i.e., the physical substructure. Moreover, to monitor the seismic performance of the pipeline and harness the use of sensor technology, acoustic emission sensors are placed through the pipeline. Thus, real-time acoustic emission signals of the system under study are acquired using acoustic emission sensors. Moreover, in addition to seismic events, also a severe monotonic loading is exerted on the physical substructure. As a result, deformation levels of each critical component were investigated; and the processing of acoustic emission signals provided a more in-depth view of the damage of the analysed components.