As a novel structural control strategy, tuned mass damper (TMD) inspired passive and semi-active smart building isolation systems are suggested to reduce structural response and thus mitigate structural damage due to earthquake excitations. The isolated structure’s upper stories can be utilized as a large scaled TMD, and the isolation layer, as a core design point, between the separated upper and lower stories entails the insertion of rubber bearings and (i) viscous dampers (passive) or (ii) resettable devices (semi-active). The seismic performance of the suggested isolation systems are investigated for 12-story reinforced concrete moment resisting frames modeled as “10+ 2” stories and “8+ 4” stories. Passive viscous damper or semi-active resettable devices are parametrically evaluated through the optimal design principle of a large mass ratio TMD. Statistical performance metrics are presented for 30 earthquake records from the three suites of the SAC project. Based on nonlinear structural models, including P-delta effects and modified Takeda hysteresis, the inelastic time history analyses are conducted to compute the seismic performances across a wide range of seismic hazard intensities. Results show that semi-active smart building isolation systems can effectively manage seismic response for multi-degree-of freedom (MDOF) systems across a broader range of ground motions in comparison to uncontrolled case and passive solution.