Seismic analysis is considered as an important aspect of the design of high-rise buildings, particularly in earthquake prone areas. The structural system choice can have a considerable impact on the building seismic response. The goal of this study is to compare the seismic behavior of multiple slab systems used in a multi-story building in Saudi Arabia's Madinah region. This study's goal is to determine the most effective and efficient slab system performance in a seismic zone. The ETABS V20.3 program was used in this work to model and assess the seismic response of three different types of slab systems: flat, solid, and hollow blocks slab types. Many earthquake aspects, including story displacement, base shear, story drifts, column forces, and bending moments, are estimated for each system. The study examines and assesses each system's seismic response, and the conclusions are given and discussed. According to the findings, the choice of slab system has a considerable impact on the seismic reaction of the building. The hollow block system has the least base shear value and bending moments, while the flat slab system has the greatest. The values in the solid slab system are in the middle. In terms of story displacement and column forces, the study additionally indicates that the hollow block type system performs effectively in terms of story drifts, however, the solid slab system outperforms the others. The study's findings can assist designers and engineers to determine the best slab system for multistory buildings in seismic-prone areas by providing important insight and suggestions.