To solve the problem of serious roller wear and improve the smoothness of the sliding door motion process, the rigid-flexible coupling multi-body model of the vehicle sliding door was built in ADAMS. Force boundary conditions of the model were determined to meet the speed requirement of monitoring point and time requirement of door opening-closing process according to the bench test specification. The results of dynamic simulation agreed well with that of test so the practicability and credibility of the model was verified. In the optimization of the ride comfort of the sliding door, two different schemes were proposed. The one was to optimize the position of hinge pivots and the other was to optimize the structural parameters of the middle guide. The impact load of lead roller on middle guide, the curvature of the motion trajectory and angular acceleration of the sliding door centroid were taken as optimization objectives. In the first scheme, multiple sets of sample models were obtained by using orthogonal experimental design and approximate surrogate models were established with the method of RSM, Kriging and RBF. However, the optimum solution couldn’t be obtained because the optimization objectives are highly nonlinear with respect to the design variables. To solve the problem, an improved optimization method of hierarchical encryption was adopted and obtained the optimum solution finally. In the second scheme, the structural parameters with the best ride performance was obtained by using the evaluation function method. The proposed study improves not only the ride comfort of the sliding door, but also has great significance for the preliminary design and development of the sliding door.