The present paper investigates the effect of changes in wheel primary Angles such as Camber and Toe Angles on the fatigue life of vehicle steering knuckle under multi-input random non-proportional 3D stress components. In order to develop real loading conditions for the steering knuckle, the localizing equivalent road as a combination of some rough roads (ISO road classification B-F for highway out of town, urban highway, urban asphalt, soil road, and flagstone, respectively) based on statistical data collected from different cities by utilizing a general questionnaire including road type and vehicle velocity was considered. Then, the various actual load histories obtained through multi-body dynamics analysis of a full vehicle model were applied on several points of the component. The fatigue life of steering knuckle was predicted by using some prominent multi-axial fatigue criteria for non-proportional loading, rain-flow cycle counting algorithm, and Palmgren-Miner damage accumulation rule. Finally, the effect of different values of wheel Angles on the fatigue life of the steering knuckle was examined. The results showed that the highest and lowest fatigue life of steering knuckle are related to the values of 2 positive and negative degrees of camber Angle, respectively. The stress level is reduced in the various equivalent load histories by changing the toe Angle to 0. 2 negative, resulting in an increase in the fatigue life of steering knuckle.