In order to enhance the aesthetical appearance of multi-storey buildings, the presence of setbacks is very common nowadays in this modern age of life. Meanwhile, the increasing occurrence of seismic events has emphasized the requirement for accurate assessment of the seismic performance of reinforced concrete (RC) multi-storey buildings. During earthquakes, the setback buildings are highly vulnerable because of their vertical geometry and mass irregularity. Generally, buildings are analysed under seismic loadings without considering the effects of soil-structure interaction (SSI), which is not an ideal practice. In this present research, a comprehensive effort has been made to assess the seismic performance of RC setback multi-storey building models with and without SSI. Several configurations of setback building models have been analysed in this study by the static and dynamic methods of seismic analysis using finite element software under medium soil conditions in a high-risk seismic zone. A regular symmetrical RC building has also been considered as a control model to prepare a comparative study. Key structural response parameters like time period, base shear, storey displacement, drift, stiffness, etc. are estimated to assess the seismic performance of these structural models. The obtained results demonstrate that the criticality increases with the increase in setback irregularity in the building under seismic loadings. These results also emphasise the importance of SSI consideration for analysing the structural responses.