Fixed base structures subjected to earthquake forces are prone to various issues, such as the attraction of greater forces to structure, amplified accelerations to non-structural components, expensive design for better seismic performance, and so forth. Base isolation applied at the foundation of vulnerable structures is a radical bypass from the conventional approaches utilized by structural engineers. However, the practical implementation of passive base isolation is constrained by factors such as large displacements at isolation level, uplifting forces at isolators, and vulnerability to unpredictable and versatile earthquakes. This study is focused on the evaluation of the smart base isolation system under various harmonic and earthquake loadings. The proposed system employs a magnetorheological elastomer (MRE)—a class of smart materials, based on an adaptive isolation layer under the building structure for its vibration control. The building is idealized as a five-degree-of-freedom (DOF) structure with the mass lumped at each storey. The stiffness of the MRE isolation layer is adjusted using the linear quadratic regulator (LQR) optimal feedback control algorithm. A total of 18 simulations have been performed for the fixed base, passively isolated, and MRE-based isolated structures under a series of earthquake loadings of both a near-fault and far-fault nature for analyzing a total of 306 responses of the structures. The simulation results indicate that MRE-based isolation has significantly reduced all the responses compared to the passively isolated structure for both the near-fault and far-fault earthquake loadings. For harmonic loading, however, the passively isolated structure outperformed the MRE isolated structure in terms of storey drift and acceleration responses.