In the present research, similar and dissimilar resistance spot welding (RSW) process of St12 and galvanized steel sheets with thickness of 0.9 mm was investigated. The experiments were carried out based on the statistical design of experiments (DOE) approach to investigate the effect of RSW parameters on the welding quality, achieving the mathematical regression equations and predicting the new results. Welding time and electrode force were considered as the input process variables while the tensile-shear strength of the joints was considered as the process response. By comparing three RSW types, galvanized steel has the highest tensile-shear strength. Statistical analysis shows that tensile-shear strength is increased with increasing electrode force and welding time. Good agreement between the verification tests and the optimization results revealed that the statistical modelling would be appropriate for RSW process. Welding time (T) = 5 s and electrode force (P) = 925 N, welding time (T) = 5 s and electrode force (P) = 1100 N and welding time (T) = 3 s and electrode force (P) = 925 N were obtained as the optimum settings for similar RSW of St12, dissimilar RSW of St12 to galvanized steel and similar RSW of galvanized steel, respectively.