Spot weld layout is critical to structural performance of vehicle and its design is also subject to manufacturing constraints. In this study, using thin-walled tube crash as an example, we establish the relation between structural performance and weld layout design with manufacturing constraints from resistance spot welding. First, a straight tube crash performance is evaluated as a function of flange width, weld distance to flange corner, and weld pitch, without consideration of manufacturing constraints. All these parameters exhibit certain influence on the deformation mode and the energy absorption capacity. Then, an S-shaped tube is studied in the design optimization of weld layout by adding manufacturing constraints. The proposed approach can determine optimized results by simultaneously considering crash performance and manufacturing constraints. It is also concluded that weld layout has more significant influence on crash performance in straight tubes than in S-shaped tubes.