A modified skyhook damping (MSD) control strategy for multi-axial heavy truck suspension system based on orthogonal test was put forward. It could improve the road friendliness and ride comfort of the truck simultaneously, as a consequence, ride fatigue was alleviated and road life was prolonged. A multi-DOF model of four-axial heavy truck-road system was developed in ADAMS based on vehicle dynamics and functional virtual prototype (FVP), and the model was validated through a ride comfort test. In order to improve the truck performance preliminarily, proper air suspensions were chosen to replace the tandem suspension on the driving axles. Subsequently, semi-active, active MSD control were applied to the whole suspension system respectively using co-simulation of ADAMS and Matlab, and control parameters which ensured best integrated performance of the truck were chosen based on range analysis and variance analysis of orthogonal test. The simulation results indicated that ride comfort of the active MSD control truck was superior to the semi-active MSD control truck, however, the road friendliness were comparable. In addition, MSD control had a strong robustness to road level.