Masonry buildings in high-intensity seismic and cold regions of China face the dual challenges of frost heaving and seismic hazards. To explore the potential of a sand cushion instead of the frozen soil layer to deal with these problems, a cost-effective sand cushion-based Geotechnical Seismic Isolation System (GSI-SC) was developed in this study, where a sand cushion is introduced between the structural foundation and natural soil, while the space around the foundation is backfilled with sand. Shaking table tests on a one-story masonry structure equipped and non-equipped with the GSI-SC system were undertaken to investigate its effectiveness in seismic isolation, where the input wave adopted the north–south component of the EL Centro wave recorded in 1940, and the peak input acceleration (PIA) was set as 0.1 g, 0.2 g, and 0.4 g. It is found that the GSI-SC system significantly reduced the seismic response of the structure, effectively achieving seismic isolation. For a PIA of 0.4 g, the GSI-SC system reduced the acceleration of the roof panel and the inter-story displacement of the structure by 33% and 39%, respectively. Numerical simulations were performed to evaluate the seismic response of buildings equipped and non-equipped with the GSI-SC system. The simulation results matched well with the experimental results, verifying the effectiveness of the newly developed seismic isolation system. The GSI-SC system can provide the potential to reduce frost heave and earthquake disasters for buildings in high-intensity seismic and cold regions.