To quantify the need for the connection of a lightweight polymer in the automotive industry, the study on laser transmission spot welding of material PMMA for vehicle by NdYAG pulse laser is conducted. The mathematical model of the process parameters with the maximum tensile force and molten pool diameter is established by the response surface method, and it can be used to optimize and analyze the experimental design. The interaction effects of key parameters including voltage, frequency, stand-off distance, and exposure on the joint performance and the mean weld diameter are analyzed, and the optimization analysis is carried out based on two kinds of optimization criteria. The results show that the voltage and frequency can affect the joint performance by controlling the laser power, and the latter has a significant influence on laser transmission spot joining performance. When the laser power becomes higher, the energy density is more concentrated. In that case, if the laser action time increases, it is easy to initiate ablation or even penetration of samples. In the process of optimization, the relative error between the predicted value and the experimental one is less than 8%, so the predicted results of parameters optimization are consistent with the experimental ones. Above all, this study provides an effective direction to enhance the bond quality and minimize the bond cost.