This paper presents a series of hexagonal cyclones with hexahedral outer tube and outer cone parts. By comparison with Hoffmann cyclone and square cyclone, we confirm the submicrometer particle separation performance of the hexagonal cyclone separator based on the computational fluid dynamics method. The Reynolds stress turbulence model combined with the discrete phase model is used to simulate the three-dimensional gas cyclone separator. The simulation results of the hexagonal cyclone demonstrate an excellent balance of transient separation and swirling flow separation. Two types of optimized hexagonal cyclones are designed, and three parameters are introduced. The results indicate that increasing the hexagonal twist angle and hexagonal outer body round corner diameter leads to higher overall pressure drop and lower collection efficiency in the hexagonal cyclone. The particle residence time in unit volume of the hexagonal cyclone is shorter, and the wall wear rate was lower as well. This represents a substantial potential savings in energy and costs.