Quantitative prediction of penetration leakage rate has not been reported so far. The theoretical prediction method of leakage rate of typical penetration static seal structure of closed structure is studied. Based on porous media seepage mechanics, the relationship between leakage rate and microstructure parameters is established, and a new prediction model of the leakage rate of sealing structures is proposed. Then, the relationship between seal-specific pressure and microstructure parameters is obtained by the Hertz contact mechanics model. Finally, the leakage rate calculation, which is independent of any experimental data, is obtained innovatively. The new model is used to predict the leakage rate of penetration, and the theoretical prediction results are compared with the experimental measurement results. It is proved that the two agree well, which verifies the effectiveness of the model. The prediction model based on this method can well reflect the effects of rough surface morphology, material mechanical properties, sealing load, high temperature, and high pressure on the leakage rate. The leakage rate prediction model proposed in this paper is independent of the experimental regression coefficient and can realize the conversion relationship between different sealing media, sealing materials, and working conditions.