This research presents a comprehensive study aimed at investigating the influence of different cyclone geometries on the flow field and performance in gas−bioparticle flows. Five distinct cyclone designs, including Stairmand high-efficiency (St 1 ), Stairmand high-flow (St 2 ), Swift high-efficiency (Sw 1 ), Swift highflow (Sw 2 ), and typical Lapple (TL), were involved. The investigation utilized a combination of computational fluid dynamics (CFD) and the discrete element method (DEM) to model the gas−particle behavior. The DEM accounted for the motion of individual particles using Newton's equations, while the CFD solved the Navier−Stokes equations to model the gas flow as a continuous medium. This numerical model successfully simulated the cyclone performance under three-dimensional (3D) true shape modeling of large-sized nonspherical bioparticles considering the particle−particle and particle−wall interaction forces. The experimental validation and verification of the model demonstrated an acceptable agreement with the simulated data. The findings revealed that cyclone dimensions significantly impacted both performance and particle behavior even when operating under identical conditions. Cyclones with matching dimensions between the bottom and vortex finder exhibited improved separation efficiency, while an increase in the vortex finder's diameter led to decreased efficiency, as in St 2 and Sw 2 cyclones. A comprehensive force analysis pinpointed regions of intense particle−wall collisions, predominantly at the cone wall apex and the wall opposite the cyclone inlet, particularly evident in St 1 , Sw 1 , and TL cyclones. Notably, particle−particle interaction forces played a crucial role in cyclone performance with increased separation efficiency observed due to particle collisions. The particle−gas forces, including drag and pressure gradient forces, were mainly affected in the inlet region and extended into the cylindrical part. The pressure gradient force exhibited a minimal impact on particle behavior. Among the cyclone designs tested, the Sw 1 cyclone demonstrated outstanding performance, achieving an impressive effectiveness of 94.4% under the given operational conditions. These findings provide a better understanding of the working mechanisms of gas−particle cyclones and similar swirling multiphase flow systems, allowing for improved optimization.