Three-dimensional isolation system (3DIS) has been increasingly applied to civil structures with small height-width ratios, but is rarely employed in the multistory and high-rise buildings due to the lack of efficient control strategy for the rocking effect. In this paper, a simplified analysis model of 3DIS was established firstly to bring insights into the coupled motion mode caused by the rocking effect, and the influence of damping ratio and height-width ratio on the modal frequency was revealed. Then, aimed at weakening rocking motion and improving the seismic isolation efficiency, a novel multi-dimensional earthquake isolation and mitigation device (MEIMD) was proposed, and both the design composition and design principle were given in detail. To validate the effectiveness of MEIMDs, a full-scale four-story frame with a height of 13.05 m and a weight of 70 tons was produced for horizontal shaking table tests. The experimental results indicated that after adopting MEIMDs, the first-order modal frequency was 1.7 Hz, with 68% decrease compared with that of the prototype structure, and the first-order modal damping ratio was above 0.23, about eight times that of the prototype structure. Moreover, the horizontal peak acceleration was significantly decreased for each floor with a maximum reduction of 49%, while the maximum horizontal displacement and rocking response were obviously lower than the limit value specified by building codes. Therefore, the MEIMDs can not only efficiently isolate the earthquake energy, but also ensure the sufficient dynamic stability of the system. This study sheds light on the real coupled horizontal-rocking response of the base isolation system with MEIMDs, and can promote the development and application of 3DIS in multistory and high-rise buildings.