Automotive door sealing system isolates passenger compartment from water, dust and wind noise. It has the most direct influences on door-closing performance, which is determined by cross-section design in terms of its appropriate Compression Load Deflection (CLD) property. Traditional sealing structure has uniform geometrical cross-section. It has the shortcomings of bad fitting in corner parts with large curvatures, causing inaccurate door-closing effort design. Regarding the door panel׳s complex 3D profile, numerical analysis and optimal design for new sealing with variable cross-section are developed in this paper. Firstly, the whole sealing is partitioned into several parts. For four nearly straight segments, conventional 2D numerical analysis can still be used to obtain desired geometrical configuration. For other four curved corner parts with large curvatures, 3D numerical analysis of door closing is applied. Secondly, 2D geometrical cross-section optimization is proposed. Instead of three variables in previous research, five variables are selected for featuring cross-section geometry and used for next CAD reconstruction with more precision. After comparison between Back Propagation (BP) neural network and the Kriging surrogate model, BP neural network which performs better and efficient in this automotive design optimization field is applied for extracting nonlinear mapping between five cross-section parameters and compression load, which were parallely optimized by Genetic Algorithm (GA) and its efficiency and accuracy are compared with another evolutionary algorithm of Particle Swarm Optimization (PSO). Thirdly, 3D numerical modeling of four curved corner parts׳ closing process is realized, of which twisting and bending effects during seal assembly are taken into account, thus minimizing theoretical error and producing more realistic solution. Consequently, the desired geometrical configurations for both straight parts and corner parts satisfying designated CLD property can be obtained and the whole sealing can be achieved with variable cross-section, resulting in an ideal door closing effort. Finally, a Matlab-based platform has been developed to assist the design and optimization process. Experiment and case study indicates that it provides an effective method for new door sealing design with variable cross-section.