The noise reduction of air-conditioning systems has gradually become an urgent problem with the comfortable requirement of driving, and the muffler is a commonly used noise reduction equipment for air-conditioning pipeline. In this article, the transmission loss of prototype muffler is co-simulated at different speeds. For optimizing the muffler, a new method that combines orthogonal optimization and detailed optimization is proposed. In orthogonal optimization, the multi-objectives orthogonal test is used to analyze the effect of four structural parameters (the shoulder height, the length of the cavity, the diameter of cavity, and the length of intubation) on the average transmission loss, the transmission loss at 1120Hz, and the frequency band width below 4dB. The influence of different factors on the transmission loss is studied at different speeds, and it found that the length of intubation has a significant impact on the transmission loss. In detailed optimization, the method is characterized by rapidity in the design of air conditioning system of vehicle, and the final optimization model is determined. The results show that the optimized structure is better than the original structure. The maximum reduction of average noise can reach 11.99dB, and the maximum noise reduction at 1120Hz reach 8.58dB.