The U.S. Department of Energy National Energy Technology Laboratory's (NETL) 50 kWth chemical looping reactor (CLR) has an underperforming cyclone, which was designed using empirical correlations. To improve the performance of this cyclone using computational fluid dynamics (CFD)-based modeling simulations, four critical design parameters including the vortex tube radius and length, barrel radius, and the inlet width and height were optimized. NETL's open source multiphase flow with interphase exchange (MFiX) CFD code has been used to model a series of cyclones by systematically varying the geometric design parameters. To perform the optimization process, the surrogate modeling and sensitivity analysis followed by the optimization capability in nodeworks was used. The basic methodology for the process is to employ a statistical design of experiments (DOE) method to generate sampling simulations that fill the design space. Corresponding CFD models are then created, executed, and postprocessed. A response surface is created to characterize the relationship between input parameters and the quantities of interest (QoI). Finally, the CFD-surrogate is used by an optimization method to find the optimal design condition based on the objective and constraints prescribed. The resulting optimal cyclone has a larger diameter and longer vortex tube, a larger diameter barrel, and a taller and narrower solids inlet. The improved design has a predicted pressure drop 11 times lower than the original design while reducing the mass loss by a factor of 2.3.