Nowadays, zero discharge of flue gas desulfurization (FGD) wastewater in coal-fired power plants has attracted great attention from all over the world. In this work, the effects of initial particle size of droplets (A), nozzle atomization cone angles (B) and initial velocity of droplets (C) on the evaporation characteristics of FGD wastewater in the spray drying tower of a 600 MW coal-fired power plant were studied numerically, and the interaction of influencing factors on evaporation characteristics of wastewater was investigated using response surface methodology (RSM). Moreover, the quadratic regression equation of coded factors with the maximum residence time of droplets (T) was given and the optimized values of each influencing factor were obtained. The results show that A, B, C, AC, A2 are significant model terms. The optimal operating parameters are considered to be: A = 60.109 μm, B = 90° and C = 150 m/s, with the corresponding T = 0.068 s. This study is expected to provide some reference for the engineering application of spray drying technology in the zero discharge of FGD wastewater of coal-fired power plants.