The main purpose of this research is to investigate the optimal design of pipeline diameter in an air brake system in order to reduce the response time for driving safety using DOE (Design of Experiment) method. To achieve this purpose, this paper presents the development and validation of a computer-aided analytical dynamic model of a pneumatic brake system in commercial vehicles. The brake system includes the subsystems for brake pedal, treadle valve, quick release valve, load sensing proportional valve and brake chamber, and the simulation models for individual components of the brake system are established within the multi-domain physical modeling software- AMESim based on the logic structure. An experimental test bench was set up by connecting each component with the nylon pipelines based on the actual layout of the 4×2 commercial vehicle air brake system. The experimental data of the transient pressure in both secondary and primary brake circuits was measured to verify the simulation accuracy and the positive results of the validation show a potential for investigating the most suitable parameter configuration of the pipeline diameter based on the computer-aided analytical dynamic models. A DOE process is then performed to determine the main factors which could greatly decrease the response time of the brake system. A remarkable improvement can therefore be obtained through altering each pipe diameter according to its direction of trend for the responses it has impact on.