Semi-dry circulating fluidized bed flue gas desulfurization(CFB-FGD) is a major industrial FGD technology. Assuming that only one desulfurizer particle is wrapped in each droplet for mass transfer and dissolution, this study proposed a two-film theory-based simplified desulfurization model, with which CFB desulfurization was performed. After model verification, this study simulated the hydrodynamics and desulfurization reaction characteristics and explored the effects of inlet SO2 concentration(A), gas velocity(B), circulating particle mass flux(C), and jet water volumetric flux(D) on the desulfurization efficiency. Simulation results coupling with response surface methodology (RSM) analysis could not only quantitatively reflect the effect degree of a single variable but also apply to the interaction between parameters, thus determining the optimal parameters. RSM results showed that D and CD were the independent and interaction parameters, respectively, that most significantly affected desulfurization efficiency. The simulation under the optimal operating parameters showed that the desulfurization efficiency was greatly improved, reaching 99.69%.