The ride comfort of the commercial vehicle is mainly affected by several vibration isolation systems such as the primary suspension system, engine mounting system and the cab mounting system. A rigid-flexible coupling model for the truck was built and analyzed in multi-body environment (ADAMS). The method applying the excitation on the wheels center and the engine mountings in time domain was presented. The variables' effects on the ride performance were studied by design of experiment (DOE). The optimal design was obtained by the co-simulation of the ADAMS/View, iSIGHT and Matlab. It was found that the vertical root mean square (RMS) acceleration and frequency-weighted RMS acceleration on the seat track were reduced about 17% and 11% respectively at different speeds relative to baseline according to ISO 2631-1.