The influence of the interaction among water-cement ratio, content of expansion agent, water reducing agent, and retarder on the compressive strength of new sealing material was studied. The Design-Expert software was used to design experiments, establish a quadratic polynomial regression model, draw response surface, and optimize parameters. The microstructure morphology of the sample is explored by scanning electron microscope (Hereinafter referred to as SEM). The research results show that the interaction between water-cement ratio and expansion agent content is the most crucial factor affecting the compressive strength of the new sealing material. Under the optimal condition of 0.4% water reducing agent, 0.04% retarder, 0.8 water-cement ratio, and 8% expansion agent, the compressive strength of the sealing material cured for 3 d and 7 d is 39.247 MPa and 41.044 MPa, with the maximum absolute error of 1.71% and 2.81%, which proves the high accuracy of the model. The main hydration products of the new sealing material are ettringite and C-S-H gel, interlacing each other to form a dense structure, which contributes to the high strength of the new sealing material.