Abstract: The main drive system of a shaft full-section tunnel boring machine (TBM) may face the impact of a high-pressure mud load caused by sudden water gushing, which imposes strict requirements on the reliability of the system seal. To prevent the possible harm caused by high water pressure confining load to the sealing system, this study proposes a new main drive sealing method based on active pressure compensation, designs a sealing device suitable for the main drive sealing runway, proposes a zero leakage sealing evaluation method combined with percolation theory and a statistical contact model, establishes a micro- and macro-scale finite element sealing structure model, investigates the sealing contact and pressure resistance characteristics under different compensatory pressures and external loads, and reveals the evolution mechanism of sealing performance under the combined action of external cavity pressure and compensatory pressure. The results indicated that effective contact between the contact surfaces was necessary for zero-leakage sealing, considering the influence of the microscopic morphology of the contact surface on the seal. The ratio of the contact area of the sealing surface to the total area is called the contact area ratio, while the ratio of the effective connected area on both sides of the contact surface to the total area is called the effective connectivity ratio. The contact area ratio corresponding to an effective connectivity ratio of 0 is called the percolation threshold. When the contact area ratio of the sealing contact stress exceeded the percolation threshold or the effective connectivity ratio dropped to zero, a sealing effect arose. The sealing ability gradually increased with the contact stress, which gradually weakened the influence of the surface topography on the sealing. The deformation of the sealing matrix caused by the external pressure gradually became the dominant factor affecting the sealing performance. When the compensation pressure was 0, the sealing pressure was lower than 0.1 MPa, and the sealing contact surface was matched with a gap. This lowered both friction and wear under the dynamic working states of normal and low pressures and extended the service life of the seal. In practice, the effective and timely removal of impurities entering the interior sealed space was achieved by utilizing the pressure difference between the internal sealing grease and exterior. Under a higher confining pressure, the new main drive seal structure exhibited better sealing ability, and under the pre-compensation mode, the sealing pressure reached 1.95 MPa at a compensation pressure of 7 MPa. Compared to the follow-compensation mode, the pre-compensation pressure effectively improved the sealing performance under low confining pressures. Simultaneously, a comparative analysis between the macro simulation results and pressure resistance test data showed that lower external pressure promoted the sealing contact stress and improved the sealing pressure under low confining pressure, whereas higher external pressure significantly affected the sealing effect of contact surface slip and matrix subsidence. Therefore, the effect of the external pressure on the matrix deformation should be considerably reduced to improve the effective sealing pressure at high confining pressures.