Aiming at the problem of difficult spherical sealing of flexible drill pipe, a spherical sealing structure suitable for flexible drill pipe is designed. The reliability of the sealing structure under the working conditions of internal pressure 30 MPa and external pressure 24 MPa is verified by numerical simulation and physical test, and based on the response surface test design method, the response surface model of the sealing structure parameters and sealing performance parameters was established, and the interaction between the parameters and the sensitivity of the three factors were analyzed. The order of sensitivity from large to small is: compression, radial interference, width of the main sealing surface. Among them, the maximum Von Mises stress of the optimized model is reduced by 16.9% compared with the original sealed structure model, which can improve the reliability and life of the structure. At the same time, the predicted value is verified by numerical simulation, and the maximum Von Mises stress error is 0.87%. The obtained results provide a certain reference for the field application of the flexible drill pipe spherical sealing structure.