To solve the problem between temperature and thermal stress of a titanium alloy piston, a multi-objective optimization method combined response surface methodology and experiment design is performed to calculate an optimal design of the titanium alloy piston. Firstly, the thermo-mechanical coupling analysis, static and dynamic characteristics analysis are carried out. The analysis results show that the thermal load has a significant influence on the piston. Secondly, the five dimensional parameters are chose as the design variables through sensitivity analysis. The piston thermo-mechanical coupling stress, deformation, mass, and the first ring groove are selected as the objective functions. By using the optimal space-filling design method, the sample points between design variables and objective functions are gained. Then, the mathematical relationship between them is obtained by the response surface method. Finally, the multi-objective genetic algorithm is employed to optimize the mathematical model. After optimization, the maximum coupling deformation decreases by 3.05%, the maximum coupling stress decreases by 27.85%, the mass reduces by 5.46%. The maximum temperature of the first ring groove reduces by 12.54%. This study can provide a reference for the piston optimization design.