<p>This study proposes a method to enhance the mechanical properties of large aluminum alloy wheels by considering the effect of secondary dendrite spacing (SDAS). First, the solidification process of these wheels was simulated using commercial simulation software, ProCAST, to predict the SDAS values. Subsequently, a wheel fatigue stress model incorporating SDAS was constructed by developing a data mapping algorithm to realize the transfer of the SDAS calculation results from the as-cast finite element model to the Abaqus static stress model. Based on the coupled solidification-fatigue stress simulation analysis, an accurate prediction of the fatigue damage region of the wheel, that is, the bolt-hole region, was realized. Finally, an optimized design of the wheel mold structure and process was performed based on the simulation results. The results showed that, after the optimized design, the tensile strength and yield elongation of the bolt-hole region increased by 16.5% and 364.7%, respectively. Metallographic observations revealed that the average SDAS score decreased by approximately 37.6%. Microstructural analysis showed that the grain refinement effect was significant after the optimized design, SDAS and microscopic defects were effectively reduced, and α-Al distribution was more uniform.</p>