The semi-dry desulfurization of slime fluidized bed boilers (FBB) has been widely used due to its advantages of low cost and high desulfurization efficiency. In this paper, the cooperative optimization of a two-stage desulfurization processes in the slime fluidized bed boiler was studied, and a model-based optimization strategy was proposed to minimize the operational cost of the desulfurization system. Firstly, a mathematical model for the FBB with a two-stage desulfurization process was established. The influences of coal slime elements on combustion flue gas and the factors that may affect the thermal efficiency of the boiler were then analyzed. Then, on the basis of the developed model, a number of parameters affecting the SO2 concentration at the outlet of the slime fluidized bed boiler were simulated and deeply analyzed. In addition, the effects of the sulfur content of coal slime, excess air coefficient, and calcium to sulfur ratio were also discussed. Finally, according to the current SO2 emission standard, the optimization operation problems under different sulfur contents were studied with the goal of minimizing the total desulfurization cost. The results showed that under the same sulfur content, the optimized operation was able to significantly reduce the total desulfurization cost by 9%, consequently improving the thermal efficiency of the boiler, ensuring the stable and up-to-standard emission of flue gas SO2, and thus achieving sustainable development.