Cyclones are generally operated in series when the efficiency of a single cyclone is not sufficient for the process. This study firstly used computational particle fluid dynamics (CPFD) to simulate the gas-solid two-phase flow characteristics in a two-stage series cyclone separator. The separation efficiency and distribution of energy consumption was interpreted by analyzing particle distribution characteristics. Secondly, the structure of the two-stage cyclone separator was optimized via response surface methodology (RSM) to make up for the disadvantage that the distribution of the separation load was nonuniform. The results showed that the grade efficiency for 3 mu m of the first-stage cyclone separator was increased from 45.408% to 59.932% compared to the original model. The pressure drop of the first-stage cyclone separator is about 2.147 kPa while the second-stage cyclone separator is about 2.774 kPa. It can be seen that the overall optimized two-stage cyclone separator has the advantages of high efficiency, low energy consumption and load-balanced separation performance. (C) 2020 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.