In this paper, a mathematical model based on the two-fluid frame model coupled with the population balance model which considers the aggregation of particles and droplets in detail for cyclonic spray dedusting is proposed. The model is applied to study the characteristics of multiphase flow field and the effects of the gas velocity, spray volume, and particle concentration on the removal efficiency. In addition, the simulation results are verified by the experimental data. The results suggest that the turbulence kinetic energy increases near the wall as the inlet velocity increases, and the spray region increases as the spray volume increases. This is conducive to turbulent mixing of the particles and droplets, and the agglomeration efficiency of the particles is improved, so the particle size increases, and the particle removal efficiency increases to 99.7% by simulation results are within the allowable range of error (about 99–99.5% in dedusting efficiency by experimental data). As the particle concentration increases, the particle removal efficiency initially increases, then decreases and reaches the highest value at 2 g/m3, which is due to the limited adsorption efficiency of the spray droplets. The results are helpful for providing a theoretical basis for spray to promote agglomeration of particles and improving the dust removal efficiency in the swirl field.