Seismic isolation, a novel technique for mitigating seismic forces, has gained widespread adoption. However, there is limited application and research on the use of this technology in twin-tower shear-wall structures with an enlarged basement (2TSSLB). The primary objective of this study is to investigate the effectiveness of base isolation in 2TSSLB structures. Non-isolated and isolated versions of a 2TSSLB structure were modeled using ETABS software, and then response spectrum and time history analyses were conducted. By comparing their story shear force, maximum story drift, and maximum story acceleration under earthquakes at the basic fortification intensity within the 8-degree region, the effectiveness of earthquake isolation can be assessed. The results indicate that the utilization of base isolation in a 2TSSLB structure leads to a significant reduction in story shear force (largest reduction of 53%), maximum story drift (48% average reduction), and maximum story acceleration (73.5% average reduction), particularly at the uppermost level of the building. This phenomenon may be attributed to the amplification of seismic response caused by the whipping effect of the topmost floor; however, it also signifies that base isolation can enhance the seismic performance of such 2TSSLB structures. Even at the highest floor, where earthquake response is intensified due to the whipping effect, significant earthquake control effectiveness is observed after isolation. This study will serve as a valuable reference for designing 2TSSLB structures and provide support for further research on the effectiveness of different isolation schemes in such structures.