S-zorb adsorption desulfurization technology is one of the most important technologies to produce the ultra-low sulfur content gasoline. However, the short operation cycle of the turbulent bed reactor limits the wide application and efficient production of S-zorb process. The main reason is that the fine particles produced by the circulation and attrition of absorbent particles are easily carried upwards to the disengager and then gradually deposited on the filter, leading to the blocking and shutdown of the top filter. In order to improve the design of S-zorb reactor and reduce the entrainment of fine particles, a deep understanding of hydrodynamic behaviors in the reactor is very necessary. In this work, a series of multiscale CFD simulations of the S-zorb reactor with absorbent large particles and fine particles were carried out and the optimization schemes were proposed. As the drag force played very important role in predicting heterogeneous gas-solid fluidized flows, the effects of drag models, i.e., the EMMS-bubbling model and EMMS-ANN model were first investigated. It was found that using both the EMMS-bubbling model and EMMS-ANN model can reasonably predict the flow distribution of absorbent particles and segregation behaviors. Compared to using the EMMS-bubbling model, using the EMMS-ANN model over-predicted the entrainment of fine particles. Then a series of design modification schemes for reducing entrainment of fine powder were investigated. It was found that increasing the height of the disengager from 0.848 to 1.150, the radius of the disengager from 0.909 to 1.212 or adding a horizontal pipe for discharging solids can help reduce the carryover of fine powders. Among these modification schemes, the increase in the disengager radius and adding a horizontal pipe at the transitional section between the reaction zone and disengager were the most effective to reduce the carryover of fine particles. These findings were very helpful for optimization of S-zorb fluidized reactor and process upgrading.