Abstract: The existing research results of high-rise base-isolation structures without considering high-order effects may have serious safety risks. Thusly, revealed is the working mechanism of the coupling between the high-order effect and the lift-off sway of the high-rise foundation isolation structure. A simulated seismic shaking table test is carried out, a finite element model is established, and the simulation results are compared with the test results to obtain the seismic response of the high-rise foundation isolation structure. Based on the results of seismic response analysis, a targeted vibration control target is formulated and the corresponding vibration control scheme is put forward. Finally, engineering suggestions are proposed. The results show that: compared with not considering the high-order effect, the high-order effect can significantly enhance the lift-off sway effect, and the isolation support is easier to enter the tension state. The limit value of the tensile seismic influence coefficient of the isolation support decreases, and the overall overturning trend of the structure is advanced. Different from the linear elastic state of the superstructure without considering the high-order effect, the high-order effect causes obvious abrupt change at the high position of the superstructure. Under the combined effect of the high-order effect and the lift-off sway effect, the seismic response of the isolation layer is amplified by about 40% compared with that without considering the high-order effect. Under different seismic conditions, the tensile stress of the isolation layer does not meet relevant regulatory requirements. Under the action of rare earthquakes, the isolation layer and the abrupt region of the superstructure may cause serious damage, and the structure may overturn under the action of rare earthquakes. Two vibration control schemes are also proposed, the base-TMD hybrid isolation scheme and the base-tension-TMD joint control scheme, to eliminate the high-order effect of high position mutation and, to reduce the seismic response of the isolation layer to 40%~70% of the original structure, effectively to suppress the lift-off sway effect, and to ensure the safety of this type of structure under the action of earthquakes.