The drainage design of main cargo compartment is of great significance to the safety of cargo aircraft. Therefore, the drainage design method of main cargo compartment is studied in this paper. First, through the analysis of the drainage scenario, the factors that need to be considered in the drainage design of the main cargo compartment are comprehensively identified. Secondly, the drainage path and drainage holes are optimized. The operation scenario of cargo aircraft determines the layout design of main cargo compartment drainage path. Rain/snow entering the main cargo compartment, water on the ULD (Unite Load Device) and water seepage of the cargo determine the drainage volume of the main cargo compartment. The drainage rate of the main cargo compartment is determined by the requirements of the cargo aircraft in different operating stages. In summary, combining with the engineering experience, this paper proposes a novel overall design method of the main cargo compartment drainage scheme of large cargo aircraft through theoretical analysis and test. The results show that the design method in this paper can meet the design requirements, and can provide a reference for the drainage design of cargo aircraft.