The general trend in the development of the automobile industry is toward lightweight vehicles, because weight has an important role in determining the performance and quality of vehicles. The body in white (BIW) refers to the stage in automotive design or automobile manufacturing in which a car body’s sheet metal components have been welded together but before the moving parts (doors, hoods, deck lids, and fenders), motor, chassis sub-assemblies, and trim (glass, seats, upholstery, electronics, etc.) have been added and before painting. In this paper, we propose an approximate model optimization for the lightweight design of the lower body structure that is based on a sequential quadratic programming algorithm. The proposed comprehensive multi-objective optimization method is used to minimize the body weight without reducing the performance, i.e., the bending and torsion stiffness of the BIW. Firstly, in the conceptual design stage of the BIW, the load transfer path of the BIW is determined using topological technology. The load transfer path is used to guide the structural design and layout of the lower vehicle body. Then, combined with implicit parametric modeling technology, the full parametric BIW model is established, and the size, position, and thickness of the cross section of the lower vehicle body are determined by a multidisciplinary optimization method, and the initial design of the vehicle body weight is reduced. Secondly, the test scheme is designed, and the approximate model of the response surface takes the bending and torsional stiffnesses and the mass of the BIW into consideration. Thirdly, the sequential quadratic programming algorithm combined with the multidisciplinary collaborative optimization algorithm is used to carry out the multi-objective optimization design of the BIW structure and obtain the Pareto optimal solution set. Our results show that the proposed method reduces the weight of the vehicle lower body by 4.07 kg.