•A full-scale shaking table test on prefabricated nuclear power industrial buildings (NPIBs) through a hybrid isolation system (HIS), incorporating natural-rubber bearings (NRBs) and nonlinear fluid viscous dampers (NFVDs), was designed and conducted.•The shaking table test validated the stable dynamic behavior of the proposed HIS, in controlling structural transient acceleration, bearing lateral and residual deformation responses.•A comprehensive parametric study was carried out, revealing the influences of key NRB and NFVD design parameters on the isolation efficiency.•Design recommendations for the NPIBs isolated by the HIS are first proposed, providing an efficient yet economical strategy in practice for both structural acceleration and bearing deformation control. A typical hybrid isolation system (HIS) incorporating natural-rubber bearings (NRBs) and nonlinear fluid viscous dampers (NFVDs) is proposed for seismic protection of critical equipment in nuclear power industrial buildings (NPIBs) under strong earthquakes. Design procedure with a parametric study towards the HIS considering various stiffness and damping values is first investigated via extensive nonlinear time history analyses. Then a preliminary recommendation for the specific structural demands of the considered system is proposed to direct the seismic design for both member- and system-level tests. Through a suite of full-scale shaking table tests on two typical NPIBs, the efficiency and reliability of the HIS are verified, in comparison to the structure with conventional rubber isolation system (RIS). The shaking table test results exhibit a superior behavior of the HIS in structural dual control strategies, i.e., transient acceleration control in critical equipment and bearing deformation control. Also, the HIS presents stable and resilient performances in both negligible residual bearing deformation and undetectable damage to structural/nonstructural components (containing the seismic isolated devices, i.e., NRBs and NFVDs). Finally, a three-dimensional finite element (FE) structural model and a single-degree-of-freedom (SDOF) system are successively developed to simulate the dynamic responses of the test structures. The well-validated SDOF FE model, serving as a reliable alternative for the isolated NPIBs, can be further utilized to facilitate practical design.