Purpose <p>This study aims to investigate the combined effects of uneven foundation settlement and multi-directional seismic action on the dynamic response and damping performance of three-dimensional (3D) base-isolated liquid storage tanks, and to assess the mitigation effectiveness of 3D isolation technology.</p> Methods <p>A liquid storage tank located on a Class III site is numerically modeled, considering liquid-solid-soil interaction. Seismic wave reflection and propagation are simulated using an artificial viscoelastic boundary, while uneven settlement is introduced via initial displacement applied at different zones (central and edge) of the tank foundation. The dynamic responses under multi-directional seismic excitation are systematically analyzed..</p> Results <p>The results indicate that uneven settlement significantly aggravates the dynamic response of non-isolated tanks, whereas the 3D isolation system effectively mitigates these adverse effects. The settlement at the edge region of the tank bottom causes more severe consequences than central settlement. Furthermore, multi-directional seismic input is shown to intensify the negative influence of uneven settlement. Both the dynamic response and the damping ratio of the 3D isolation system increase with greater settlement magnitudes.</p> Conclusions <p>Uneven foundation settlement considerably affects the seismic safety of liquid storage tanks, and the use of 3D base isolation can alleviate these effects. It is recommended to closely monitor edge settlements and prioritize maintenance in practical engineering to ensure structural integrity under combined environmental loads.</p>