In this advanced technological era, lightweight design for fuel efficiency and environmental friendliness is essential for both conventional and hybrid electric vehicles (HEVs), without sacrificing the durability which is an important design factor for vehicle safety. To achieve these objectives, reduction of the structural mass of the full vehicle plays a vital role. The scope of this paper is to describe design methodologies for the vehicle differential case applied to achieve light weight and to ensure product life. The focus of this paper includes two tasks. The topology optimization and fatigue analysis of a vehicle differential case are conducted. Finite element analysis (FEA) is used to simulate the stress with constraint. After that, optimization parameters (design variables, responses, objective functions and constraints) of a vehicle differential case are selected for lightweight design by solid isotropic microstructures with penalization (SIMP) method. The optimization results revealed that the SIMP method successfully achieved 25% mass reduction of vehicle differential case. Furthermore, the second task is the fatigue analysis which is usually used during the design phase to predict the future failure of components. The fatigue lives and damages of two lightweight cases obtained from topology optimization were analyzed and compared. Our proposed research methodology is expected to be useful in reducing mass and prolonging product life.