A study on transmission laser bonding of silicon with glass by NdYAG pulse laser is conducted. The mechanism of transmission laser bonding of silicon with glass is expounded. Combined with a central composite rotatable experimental design, response surface methodology (RSM) is employed to establish mathematical models of relationships among various welding process parameters and lap-shear strength as well as bond width. Then the analysis of variance is checked and these mathematical models are validated. Effects of different bonding parameters on lap-shear strength and bond width are discussed. Based on this, desirability function is introduced to optimize the parameters of the bonding process and the result of optimal experiments is verified. The results obtained indicate that the developed mathematical models can be used to show the relationship between responses and parameters. Predicted results of parameters optimization developed by desirability function are consistent with experimental results. Therefore, this study provides an effective direction to enhance the bond quality and minimize the bond cost.