A 3D numerical model of the municipal solid waste incineration (MSWI) process was constructed based on a grate furnace with a daily processing capacity of 800 tons. Fluent was used for analyzing key factors affecting the concentration and diffusion level of particulate matter (PM). According to the actual MSWI plant working condition, a 3D model of the incinerator and the waste heat boiler has been constructed under benchmarks. Key factors affecting PM generation were determined by combining mechanistic knowledge and experts’ experience. They were the combustion temperature of solid phase municipal solid waste (MSW), the wall’s PM collision mode, and the second baffle length. Subsequently, the process of resolving the 3D numerical model was delineated. Then, a univariate analysis of the aforementioned 3D model was conducted for the three pivotal factors mentioned above. Conclusively, the effect of the important factors on the number of particles at the outflow of the incinerator was analyzed via orthogonal experiments to obtain the optimal combination. PM concentration initially diminished and then rose with the increased combustion temperature of the solid-phase MSW. Furthermore, a noteworthy reduction in PM concentration was observed when the second baffle length was 12.45–12.95 m. The greatest influence on the PM concentration of the outlet was posed by the wall’s PM collision mode, followed by the second baffle length. The appropriate adjustment of the combustion temperature of the solid-phase MSW, selection of wall materials, and design of the second baffle length were beneficial for diminishing PM concentration and ensuring long-term stable operation of the MSWI process. The combinative optimality of the three key factors was acquired via orthogonal experiments, which proved the subsequent optimal control of PM concentration at the outlet.