The uniform design and response surface methodology (RSM) are applied to the multi-objective optimization of a 2-D mixed compression scramjet inlet. The set of experimental design points on the design space is selected by the uniform design, and the inlet performance is analyzed by computational fluid dynamics (CFD). Then complete quadratic polynomial response surface approximation models are constructed based on the performance analysis results and then used to replace theoriginal complex inlet performance model. The optimization is conducted using a multi-objective genetic algorithm NSGA-Ⅱ, and the Pareto optimal solution set is obtained. Results show that the uniform design and RSM can reduce the computational complexity of numerical simulation and improve the optimization efficiency.