The damage of a long tunnel is found in parts with an adverse geological structure zone under an earthquake. The phenomenon is normally the consequence of a non-uniform seismic load. Thus, to reveal the mechanism of the phenomenon, the dynamic response of the lining structure in a long tunnel passing through an adverse geological structure zone subjected to a non-uniform seismic load is mainly studied in this paper. Firstly, based on the random ground motion synthesis theory, the non-uniform ground motion acceleration−time history curves that reflect local site effects, such as traveling wave effects and attenuation effects, are generated. Secondly, the behavior of the tunnel with a different adverse geological structure zone (including different inclinations, thicknesses, and lithologies) under non-uniform seismic input is studied. Then, the impact of the different adverse geological structure zone on the internal force and safety factor of the tunnel lining is analyzed. Finally, the failure characteristics of the lining structure in the tunnel crossing through the adverse geological structure zone subjected to a non-uniform seismic load are revealed. The results show that the seismic dynamic responses significantly increase under non-uniform seismic input compared with the results under uniform seismic input, and the dynamic responses distribution along the tunnel axial is distinctly different under non-uniform seismic input. The inclination and thickness of the adverse geological structure zone have a significant influence on the internal force and safety factor of the tunnel lining, while the lithology mainly acts around the adverse geological structure zone. When the inclination angle of the adverse geological structure zone is 45°, a large number of compression-bending cracks appear in the entrance and exit sections of the tunnel, and the tunnel is in the most dangerous state.