In this paper, the seismic response analysis of the Kashiwazaki-Kariwa nuclear power plant (KKNPP, Japan) is presented. The basic earthquake scenarios correspond to a Mw4.4 aftershock that followed the Mw6.6 2007 Chuetsu Earthquake, which largely damaged the KKNPP site. A high-fidelity source-to-site earthquake simulator is exploited to generate physics-based (PBS) ground motion in 0-5 Hz frequency range (long period, LP). Based upon those results, hybrid (HYB) broad-band (0-30 Hz) ground motion at surface is rendered by exploiting Neural Networks to generate the 5-30 Hz part of the synthetic spectra (broad-band BB). The novelty of this paper are two: (1) a random fluctuation is added to the PBS LP portion of the spectrum to render 200 different input-motion scenarios; (2) these synthetic ground motion realizations are injected into a numerical model of the Unit 7 reactor building to assess its dynamic response. The wave propagation problem is solved by means of the Spectral Element Method (SEM), over a ~50.8 km × 50.8 km × 68 km domain in the surrounding of the KKNPP, with smallest grid-size of ~200 m ×200 m × 200 m. The overall numerical accuracy is granted in a 0-5 Hz frequency band. The complex regional geology is included (after verification). PBS synthetic time-histories are enriched at high frequency (5-30 Hz), exploiting ANN2BB, a 2-layer Neural Network trained on a set of strong-motion records, to predict the response spectral ordinates at short periods, based on the long period ones. Broad-band (0-30 Hz) synthetics are obtained by iterative scaling the Fourier spectra obtained via simulation, until their response spectrum matches the ANN2BB target spectrum (with no phase change). Following this strategy, 200 strong ground motion realizations are produced via quasi Monte Carlo algorithm, adding small fluctuations to the low-frequency part of the spectrum (produced by the uncertainty on the geology) before undergoing ANN2BB hybridization. The free-field ground motion realization are finally employed as input motion for the local Soil-Structure Interaction model of the KKNPP Unit 7 reactor building. The seismic response at different monitoring point on the nuclear installation is drawn by exploiting this powerful hybrid technique in order to assess the vulnerability of this critical structure and the sensitivity to the uncertainty on the regional geological model.