Aimed at a study of the mechanical property of hexagonal honeycomb space box floor structure system in long-span medium and high-rise buildings, based on specific engineering examples, a finite element analysis model of different plane floor structure layouts has thus been established by using ANSYS finite element structure analysis software, with a comparative study on the structural response of hexagonal honeycomb space box structure system and orthogonal inclined space box structure system under the action of vertical static test, followed by a research on the maximum deflection, natural frequency and overall stiffness of two different box structure floors. The results show that under the vertical load, the hexagonal honeycomb space box structure system embodies three-dimensional force transmission characteristics with a good structural performance. Compared with the orthogonal inclined space box structure system, the hexagonal honeycomb space box structure system is characterized with a smaller mid-span deflection, as well as an improved integrity and stability. According to the modal analysis method, based on the natural frequencies and periods of the two structural systems, it is concluded that the overall lateral stiffness and the flexural stiffness of the open web sandwich slab floor of the hexagonal honeycomb space box structure system are greater than that of the orthogonal inclined space box structure. From the perspective of economy, it is known that under the same functional requirements, the steel consumption of the regular hexagonal honeycomb space box floor structure system is much smaller than that of the orthogonal inclined steel-concrete box structure system, thus greatly saving the construction cost.