∆F-N curves are usually used to predict the fatigue life of spot welding in engineering, but they are time-consuming and laborious and not universal. For the purpose of predicting the fatigue life of spot welding accurately and efficiently, tensile–shear fatigue tests were conducted to obtain the fatigue life of spot-welded specimens with different sheet thicknesses combinations. These specimens were simulated by using the finite element method, and the structural stress was theoretically calculated. In the double logarithmic coordinate system, the structural stress–fatigue life (S–N) curve of spot welding was fitted by the least-squares method, based on the quasi-Newton method. The square of the correlation coefficient of the S-N curve was taken as the optimization objective, with the correction coefficients of force, bending moment, spot welding diameter, and sheet thickness as the variables. During the optimization process, three different ways were utilized to get three optimized spot welding S–N curves, which are suitable for different situations. The results show that the fitting effect of the S–N curve is improved, the data points are more compact, and the optimization effect is significant. These S–N curves can be used to predict the fatigue life, which provide the basis for practical engineering application.