As transportation networks continue to expand into mountainous regions with high seismic activity, ensuring the seismic safety of tunnels crossing active faults has become increasingly crucial. This study aimed to enhance our understanding of the impact of fault zones on the seismic behavior of tunnels and to provide optimized seismic design recommendations through a comprehensive experimental and numerical investigation. The focus of this research is the Xiangyangshan Highway Tunnel in China, which intersects a significant longitudinal fault. Large-scale shake table tests were performed on 1:100 scale physical models of the tunnel to analyze the seismic responses under various ground motion excitations. Detailed three-dimensional finite difference models were developed in FLAC3D and calibrated based on the shake table results. The tests indicated that strains, earth pressures, and accelerations experience localized amplification within 10–20 m of the fault interface compared to undisturbed ground sections. Common seismic mitigation measures, such as rock grouting, seismic joints, and shock absorption layers, were observed to effectively reduce the amplified seismic demands. Grouting, in particular, led to an average reduction of up to 56.3% in circumferential strain and 38.5% in earth pressure. It was concluded that 6 m thick grouted zones and 20 cm thick rubber interlayers between tunnel lining shells provide optimal structural reinforcement against the effects of fault zones. This study provides valuable insights for improving the seismic resilience of underground transportation corridors in seismically active regions.