As one of the important freight modes, heavy trucks need a high- strength and high-reliability drive system to carry huge goods. Therefore, the drive axle housing, a key component, significantly influences the performance and service life of vehicles, and its design and optimization have high practical significance. Firstly, this study begins by creating a geometric model of the axle housing using SW and analyzes its stress distribution under four typical operational conditions. Through static analysis, it is concluded that the most critical operational conditions are the maximum deformation of 2.151 mm and the peak stress of 272.3 MPa; in the fatigue analysis of ANSYS Workbench, the minimum life is 820,000 times. Results from both static and fatigue assessments indicate that the initial axle housing design satisfies stiffness, strength, and fatigue requirements. There is a large margin in the structure, which has certain optimization space. Considering the most dangerous working condition, the response surface optimization module of ANSYS Workbench is used with the objective of mass reduction. Finally, the axle housing is reduced by 4.09 kg; the corresponding maximum deformation is 2.262 mm, meeting stiffness criteria, while the peak equivalent stress reaches 280.3 MPa, remaining below the material's yield strength. The minimum life is about 620,000 times, and the maximum fatigue life is 1 million times, which still meets the requirements of the vertical bending fatigue test. This lightweight redesign reduces material and manufacturing costs while maintaining the requirements for deformation, stress, and fatigue strength.